1521-0081/67/4/8721004$25.

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PHARMACOLOGICAL REVIEWS
Copyright 2015 by The American Society for Pharmacology and Experimental Therapeutics

http://dx.doi.org/10.1124/pr.115.010967
Pharmacol Rev 67:8721004, October 2015

ASSOCIATE EDITOR: MARKKU KOULU

Mechanisms of Action and Persistent Neuroplasticity

by Drugs of Abuse
Esa R. Korpi, Bjrnar den Hollander, Usman Farooq, Elena Vashchinkina, Ramamoorthy Rajkumar, David J. Nutt, Petri Hyyti,
and Gavin S. Dawe
Department of Pharmacology, Faculty of Medicine, University of Helsinki, Finland (E.R.K., B.d.H., E.V., P.H.); Department of
Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Neurobiology and Ageing Programme, Life Sciences
Institute, National University of Singapore, Singapore, and SINAPSE, Singapore Institute for Neurotechnology, Singapore (E.R.K., R.R.,
G.S.D.); Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut (U.F.); and Centre for
Neuropsychopharmacology, Division of Brain Sciences, Burlington Danes Building, Imperial College London, London.
United Kingdom (D.J.N.)

This project was partially funded by the Academy of Finland, the Sigrid Juselius foundation, the Finnish Foundation for Alcohol Studies,
the Jane and Aatos Erkko Foundation, the Foundations Professor pool, and the Orion Research Foundation.
Address correspondence to: Dr. Esa R. Korpi, Department of Pharmacology, Faculty of Medicine, Biomedicum Helsinki, POB 63
(Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. E-mail esa.korpi@helsinki.fi or Gavin S. Dawe, Department of Pharmacology,
Yong Loo Lin School of Medicine, Building MD3, #04-01Y, 16 Medical Drive, Singapore 117600. Email: gavin_dawe@nuhs.edu.sg.
dx.doi.org/10.1124/pr.115.010967
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Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 875
I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 875
A. Different Forms of Neuroplasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 876
B. Short-term Neuroplasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878
C. Main Forms of Long-term Neuroplasticity: Long-term Potentiation and Long-term
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 879
1. Presynaptic Forms of Long-term Plasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 880
2. Postsynaptic Forms of Long-term Plasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 880
3. a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate
Receptor Phosphorylation.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 880
4. a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate
Receptor Trafficking. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881
D. Forms of Long-term Plasticity at Inhibitory Synapses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881
E. Developmental Maturation of the Brain in Rodents and Humans . . . . . . . . . . . . . . . . . . . . . . . . . 882
F. Developmental Neuroplasticity: Critical Periods, Reopening of Plasticity in Adults . . . . . . . . 883
G. Neurotrophins as Regulators of Neuroplasticity: Brain-Derived Neurotrophic
Factor as an Example . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 885
H. Animal Models of Drug Reinforcement and Addiction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 885
II. Actions and Persistent Effects of Specific Drugs of Abuse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 886
A. Cocaine, a Stimulant and Local Anesthetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 886
1. Persistent Ventral Tegmental Area Neuroplasticity after a Single Dose. . . . . . . . . . . . . . . 887
2. Changes in the Nucleus Accumbens Mediate Cocaine Addiction and Relapse.. . . . . . . . . 890
3. Altered Gene Expression in the Nucleus Accumbens in Cocaine Seeking and Relapse. 893
4. Progressive Involvement of the Dorsal Striatum.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 895
5. Changes in Lateral Habenula and Rostromedial Tegmental Nucleus Contribute
to Aversive Symptoms of Cocaine Withdrawal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 895
6. Complex Alterations in the PFC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 896
7. Hippocampal Functional Changes.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897
8. Bed Nucleus of Stria Terminalis and Amygdala are Involved in
Stress-Induced Reinstatement of Cocaine Seeking. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897
9. Effects of Adolescent Cocaine Exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898
10. Human Imaging Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898
11. Limited Evidence of Cocaine Neurotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 899

Drug-Induced Neuroplasticity

873

12. Potential Mechanisms in Cocaine Neurotoxicity and Neuroprotection. . . . . . . . . . . . . . . . . 900

13. Methylphenidate and Novel Psychoactive Substances.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 900
14. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 900
B. Amphetamine-type Psychostimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 900
1. Many Stimulant Amphetamines for Abuse and Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 902
2. Molecular Targets and Mechanisms of Action of Amphetamines. . . . . . . . . . . . . . . . . . . . . . 902
3. Comparison of the Mechanisms of Action of Amphetamine versus Methamphetamine. 902
4. Effects of Amphetamine at Plasmalemmal Dopamine Transporter. . . . . . . . . . . . . . . . . . . . 903
5. Regulation of Dopamine Efflux Via the Dopamine Transporter by Protein Kinase
C and Ca2+/Calmodulin Kinase II Phosphorylation, and by Reactive Oxygen Species. . 904
6. Effects on Secretory Vesicles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 904
7. Other Amphetamine Targets: Monoamine Oxidase, Tyrosine Hydroxylase, other Monoamine Transporters, Trace Amine-Associated Receptor 1, and Sigma Receptors. . . . . . . 905
8. Action of Substituted Amphetamines and Cathinones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 905
9. Action of Stimulants Common in Clinical Use. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906
10. Efficacy and Addiction Liability of Amphetamines in Clinical Use. . . . . . . . . . . . . . . . . . . . 906
11. Neuroplasticity Related to Sensitization and Addiction to Amphetamines. . . . . . . . . . . . . 907
12. Glutamate and Amphetamine/Methamphetamine Reinforcement/Extinction/Reinstatement.. 908
13. Long-term Neuroadaptation/Neurotoxicity after Exposure to High Doses of
Psychostimulants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909
a. Effects on brain structure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909
b. Effects on neurochemistry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910
c. Effects on behavior. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910
14. Limited Evidence for Long-term Effects of Substituted Cathinones in Rodent
Models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 911
15. Mechanisms Involved in Long-term Adaptation and Neurotoxicity. . . . . . . . . . . . . . . . . . . . 911
a. Oxidative stress: DA oxidation and drug metabolites as sources of reactive species.911
b. Mitochondrial dysfunction: ATP deficit, superoxide leakage, and apoptosis.. . . . . . . . 912

ABBREVIATIONS: AC, adenylyl cyclase; ADHD, attention deficit hyperactivity disorder; 2-AG, 2-arachidonoylglycerol; ALDH,
aldehyde dehydrogenase; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AMPH, amphetamine; BDNF, brain-derived
neurotrophic factor; BLA, basolateral complex of the amygdala; BNST, bed nucleus of stria terminalis; BOLD, blood oxygen level
dependent; BZ, benzodiazepine; CAM, cell adhesion molecule; CaMKII, Ca2+/calmodulin kinase II; CCK, cholecystokinin; CeA, central
nucleus of the amygdala; CNS, central nervous system; CPP, conditioned place preference; CREB, cAMP response element-binding
protein; CRF, corticotropin-releasing factor; D1R, dopamine-1 receptor; D2R, dopamine-2 receptor; DA, dopamine; DARPP-32, DA- and
cAMP-regulated phosphoprotein; DAT, dopamine transporter; DBI, diazepem binding inhibitor; DGL, diacylglycerol lipase; DOI,
2,5-dimethoxy-4-iodoamphetamine; DSE, depolarization-induced suppression of excitation; DSI, depolarization-induced suppression of
inhibition; eCB, endocannabinoid; ECM, extracellular matrix; EEG, electroencephalography; EPSC, excitatory postsynaptic currents;
ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; ETC, electron transport chain; FC, frontal cortex; fMRI,
functional magnetic resonance imaging; G9a, lysine dimethyltransferase G9a; GABA, g-aminobutyric acid; GHB, gammahydroxybutyrate; GPCR, G protein-coupled receptor; HC, hippocampus; HDAC, histone deacetylase; HFS, high-frequency stimulation;
HPPD, hallucinogen persisting perception disorder; 5-HT, 5-hydroxytryptamine, serotonin; ICSS, intracranial self-stimulation; iGluR,
iontropic glutamate receptor; IL, infralimbic cortical region; IP3, inositol 1, 4,5-trisphosphate; IPN, interpeduncular nucleus; IPSC,
inhibitory postsynaptic currents; IPSP, inhibitory postsynaptic potential; JNK, c-Jun N-terminal kinases; Kal-7, postsynaptic densitylocalized kalirin-7; KCC, potassium-chloride cotransporter; KO, knockout; LA, lateral nucleus of amygdala; LC, locus ceruleus; LDTg,
laterodorsal tegmental nucleus; LDX, lisdexamfetamine; LFS, low-frequency stimulation; LHb, lateral habenula; LSD, lysergic acid
diethylamide; LTD, long-term depression; LTP, long-term potentiation; MAO, monoamine oxidase; MAPK, mitogen-activated protein
kinase; MDMA, 3,4-methylenedioxymethamphetamine (ecstasy); MDMC, methylone; METH, methamphetamine; mGlu, metabotropic
glutamate receptor; MHb, medial habenula; MK-801, dizocilpine; 4-MMC, mephedrone; MPH, methylphenidate; MRI, magnetic
resonance imaging; MSN, medium spiny neuron; mTOR, mammalian target of rapamycin; NAc, nucleus accumbens; nAChR, nicotinic
acetylcholine receptors; NE, norepinephrine; NET, norepinephrine transporter; NFkB, nuclear factor kappa-B; NMDA, N-methyl-Daspartate; NO, nitric oxide; NOP, nociceptin receptor; N/OFQ, nociceptin/orphanin FQ; NPY, neuropeptide Y; OFC, orbitofrontal cortex;
OR, odds ratio; OX, orexin; P, postnatal day; PAG, periaqueductal gray area; PBR, peripheral benzodiazepine receptor; PCP,
phencyclidine; PET, positron emission tomography; PFC, prefrontal cortex; PI3K, phosphatidylinositide 3-kinase; PKA, protein kinase
A; PKC, protein kinase C; PKMzeta, atypical PKC; PLC, phospholipase C; PNN, perineuronal nets; PrL, prelimbic cortical region; PSANCAM, polysialylated neuronal cell adhesion molecule; PSD, postsynaptic density; Pv, parvalbumin; R, receptor; RGS, regulator of G
protein signaling; rmTg, rostromedial tegmental nucleus; ROS, reactive oxygen species; SA, self-administration; SERT, serotonin
transporter; SN, substantia nigra; TA1, trace amine-associated receptor 1; TH, tyrosine hydroxylase; THC, tetrahydrocannabinol;
TLR4, toll-like receptor 4; TPH, tryptophan hydroxylase; TrkB, tropomyosin receptor kinase B; TSPO, mitochondrial translocator
protein; VGCC, voltage-gated calcium channel; vHC, ventral hippocampus; VMAT-2, vesicular monoamine transporter 2; VTA, ventral
tegmental area.

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Korpi et al.

C.

D.

E.

F.

G.

H.

c. Excitotoxicity: glutamate receptor involvement and intracellular excitotoxic

processes.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 913
d. Hyperthermia: a catalyst of other toxic processes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 913
e. Other
factors:
inflammation,
blood-brain
barrier
disruption,
protective
preconditioning. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914
16. Evidence of Long-term Plasticity and Cognitive Effects after Stimulant Use in
Humans.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914
a. Cognitive behaviors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914
b. Brain imaging of receptors, transporters and activity/metabolism.. . . . . . . . . . . . . . . . . 915
c. Magnetic resonance imaging studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915
d. Magnetic resonance spectroscopy and analysis of postmortem tissue.. . . . . . . . . . . . . . 916
e. Prospective and experimental studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 916
17. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 917
Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 917
1. Nicotinic Acetylcholine Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 917
2. Upregulation of Nicotinic Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 918
3. Nicotine-priming Effects and Upregulation of Catecholamine Synthesis. . . . . . . . . . . . . . . 919
4. Nicotine and Neuroplasticity within the Ventral Tegmental Area. . . . . . . . . . . . . . . . . . . . . 920
5. Nicotine and Neuroplasticity in the Lateral Hypothalamic Orexin System. . . . . . . . . . . . 921
6. Nicotine and Glutamatergic Neuroplasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921
7. Nicotine and the Habenula. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 922
8. Long-term Sequelae of Adolescent Exposure to Nicotine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923
9. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924
Neural Adaptations Induced by Ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925
1. Cell Membrane Ion Channels as Primary Targets of Ethanol. . . . . . . . . . . . . . . . . . . . . . . . . 925
2. Ethanol-Induced Changes in Glutamatergic Transmission. . . . . . . . . . . . . . . . . . . . . . . . . . . . 928
3. Ethanol-Induced Changes in g-Aminobutyric Acidergic Transmission. . . . . . . . . . . . . . . . . 929
4. Ethanol-Induced Changes in Neuropeptide Mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931
5. Role of Acetaldehyde in Ethanols Reinforcing Actions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 933
6. Structural Plasticity in Alcohol Dependence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 933
7. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
Benzodiazepines and Other GABAergic Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
1. Molecular Targets for Benzodiazepines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935
2. Neuroplasticity Induced by Benzodiazepines and Related Compounds. . . . . . . . . . . . . . . . 936
3. Behavioral After-effects of g-Aminobutyric Acid A Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 939
4. Effects of Flumazenil on Benzodiazepine and Alcohol Tolerance. . . . . . . . . . . . . . . . . . . . . . 939
5. Treatment of Addictions by g-Aminobutyric Acid B Receptor Agonists. . . . . . . . . . . . . . . . 940
6. g-Hydroxybutyrate as a Drug of Abuse and a Therapeutic Compound.. . . . . . . . . . . . . . . . 941
7. Anesthetics and Neuroplasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942
8. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943
N-methyl-D-aspartate Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943
1. Ketamine: a Dissociative Anesthetic with Rapid Antidepressant Effects in Patients. . . 944
2. Phencyclidine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 946
3. Dizocilpine, a Prototypic Noncompetitive N-methyl-D-aspartate Receptor Antagonist. . 948
4. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 949
Opioid-Induced Neural Adaptations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 949
1. Desensitization and Internalization in Opioid Tolerance and Dependence. . . . . . . . . . . . . 950
2. Cellular Signaling in Opioid Tolerance and Dependence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
3. Novel Mechanisms in Between-systems Adaptations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951
4. Opioid-Induced Changes in Excitatory and Inhibitory Synaptic Plasticity. . . . . . . . . . . . . 952
5. Chronic Opioids and Synaptic Plasticity.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 953
6. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955
Cannabinoids: Multiple Mechanisms and Possible Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955
1. Endocannabinoid System as an Endogenous Lipid Messenger System.. . . . . . . . . . . . . . . . 956
2. Short-term Plasticity Involving Retrograde Endocannabinoid Signaling. . . . . . . . . . . . . . . 957
3. Long-term Plasticity and CB1 Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 958
4. Cannabinoid Effects on Brain Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 958

Drug-Induced Neuroplasticity

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5. Cannabinoid-Induced Cognitive Impairment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 959

6. Rewarding and Aversive Behaviors, Specific Actions on VTA DA Neurons. . . . . . . . . . . . 960
7. Cannabinoids during Adolescence: Increased Risk for Schizophrenia?. . . . . . . . . . . . . . . . . 961
8. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 962
I. Hallucinogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 962
1. Effects of Serotonergic Hallucinogens Are Mediated by the 5-HT2A Receptor. . . . . . . . . . 962
2. Hallucinogen ActionA Perturbation of Sensory Gating or Desynchronization
of Cortical Rhythms?... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 963
3. Behavioral Effects and Addiction Potential. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
4. Long-term Residual Effects of Serotonergic Hallucinogens: the Role of
Neuroplasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
a. Sensory processing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
b. Mood and anxiety. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965
5. Scopolamine: Another Hallucinogen Revisited for Depression. . . . . . . . . . . . . . . . . . . . . . . . . 966
6. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 966
III. General Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 966
A. Novel Methods for Future Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 969

AbstractAdaptation of the nervous system to

different chemical and physiologic conditions is important for the homeostasis of brain processes and for
learning and remembering appropriate responses to
challenges. Although processes such as tolerance and
dependence to various drugs of abuse have been known
for a long time, it was recently discovered that even
a single pharmacologically relevant dose of various
drugs of abuse induces neuroplasticity in selected
neuronal populations, such as the dopamine neurons
of the ventral tegmental area, which persist long after
the drug has been excreted. Prolonged (self-) administration of drugs induces gene expression, neurochemical, neurophysiological, and structural changes in
many brain cell populations. These region-specific
changes correlate with addiction, drug intake, and

conditioned drugs effects, such as cue- or stressinduced reinstatement of drug seeking. In rodents,
adolescent drug exposure often causes significantly
more behavioral changes later in adulthood than
a corresponding exposure in adults. Clinically the
most impairing and devastating effects on the brain
are produced by alcohol during fetal development. In
adult recreational drug users or in medicated patients,
it has been difficult to find persistent functional or
behavioral changes, suggesting that heavy exposure to
drugs of abuse is needed for neurotoxicity and for
persistent emotional and cognitive alterations. This
review describes recent advances in this important
area of research, which harbors the aim of translating
this knowledge to better treatments for addictions and
related neuropsychiatric illnesses.

I. Introduction

and ethnic groups studied in the United States. Individuals with alcohol or illicit drug abuse or dependence
in the past year constituted 5% of the adolescents aged
between 12 and 17 and more than 8% of all individuals
aged 12 or older (SAMSHA, 2014a). Of the racial/ethnic
groups studied among those aged 12 and older, Asians
had the lowest proportion of binge alcohol drinkers and
past-month illicit drug users, likely partly due to
societal/cultural traditions. These findings on rather
widespread drug and alcohol exposures at young ages
are very alarming, because brain development continues well past the age of 17 years and because the
exposure to several different drugs, such as illicit drugs,
cigarettes, and alcohol, appears to concentrate on the
same individuals (SAMSHA, 2014b). Therefore, it is
possible that harmful effects from early drug use will
prevail later in life, because drugs of abuse induce
different modulations in brain circuitries (adaptation,
plasticity, learning, and memory) due to their pharmacological actions and due to behavioral/social effects
associated with their use and settings. Thus, we will

Brain diseases are associated with an enormous cost

to affected individuals, their families, and the society. In
Europe, it has been estimated that the total yearly cost
of brain diseases in 2010 was close to 800 billion euros
(Olesen et al., 2012), of which addictions are responsible
for as much as anxiety disorders, with only dementia
and mood illnesses costing more (DiLuca and Olesen,
2014). Drug abuse produces both direct and indirect
costs to the society, although many of the drugs are also
clinically used to treat various patient groups. The
purpose of this review is to present up-to-date knowledge of the mechanisms of action of the main drugs of
abuse and to reveal the possible long-term alterations in
the nervous system associated with the use and abuse of
various drugs acting on the brain, also paying attention
to the trajectory of brain development.
Addiction is a complex phenomenon, which is not only
dependent on pharmacological mechanisms, but also
has a societal/cultural dimension. This is reflected in
the proportion of drug addiction among different age

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Korpi et al.

explore the data on different drugs and how they

persistently affect brain functions if the drug exposure
occurs during adolescence.
The review first gives a general basic introduction to
neuroplasticity. Then sections on different drugs follow
and they have different focuses, because the various
drugs do not invoke exactly similar mechanisms or
adaptations in the nervous system. The review will end
with a short general summary.
Certain mechanisms seem to be common for many
drugs, for example, activation of the extracellular
signal-regulated kinase (ERK) pathway in specific brain
structures is necessary for effects of and tolerance to
cocaine, nicotine, MDMA, phencyclidine, alcohol, and
cannabinoids after both acute and chronic treatments in
rodents (Kyosseva et al., 2001; Salzmann et al., 2003;
Valjent et al., 2004; Rubino et al., 2005; Tonini et al.,
2006; Schroeder et al., 2008). One human postmortem
brain study suggested that cocaine, cannabis, and/or
phencyclidine abuse all decrease transcription of
calmodulin-related genes and increase transcription of
genes related to lipid/cholesterol and Golgi/endoplasmic
reticulum (ER) function in the anterior prefrontal cortex
(PFC), which may underlie changes in synaptic function
and plasticity (Lehrmann et al., 2006). However, postmortem brain regional gene expression profiling in
alcohol-dependent patients has indicated widely differing sets of affected genes between different brain
regions (Flatscher-Bader et al., 2005, 2006), with alcoholics nevertheless being easily separable from nonalcoholic controls and smokers (Flatscher-Bader et al.,
2010). The same situation was found for other drugs of
abuse (Albertson et al., 2004, 2006). Significant alterations in glutamate and GABA receptor mRNAs were
found in postmortem brains of alcohol-dependent subjects, but the changes differed from one brain region to
another (Jin et al., 2011, 2014a,b; Bhandage et al.,
2014). For these obvious reasons, we reviewed the
literature for each drug according to the specific brain
regions where alterations have been observed most
commonly in preclinical experiments. These brain areas
and pathways, which serve for positive and negative
reinforcing behavioral and emotional effects and for
goal-directed and habitual drug seeking, are illustrated
in Fig. 1. However, it will be necessary in the future to
study the plasticity and mechanisms more precisely
at the level of different neuronal populations and
subpopulations.
As is usual in addiction-related reviews and research,
the dopamine (DA) mechanisms are center stage. The
reader is referred to recent reviews on various aspects
of DA as a neurotransmitter and a regulator of motor,
cognitive, and motivated behavior (Bjorklund and Dunnett,
2007; Beaulieu and Gainetdinov, 2011; Salamone and
Correa, 2012). DA is important for a wide number of
brain functions, and it will be impossible to cover each
and every aspect of the DA mechanisms in drug actions

and adaptations. The focus in this review will be more

on the neuroplasticity of the glutamate synapses on DA
neurons.
Pharmacological actions of drugs are mediated by
specific receptors. On the other hand, the effects of the
drugs of abuse are often modulated by experimental
settings and expectancies in both preclinical studies
and human experiments. Drug intake in rodents is
dependent, for example, on cage conditions, with the
effects differing between opioids and stimulants (Badiani
et al., 2011). Voluntary self-administration (SA) (selfstimulation or cocaine) induces different brain regional
activations (Porrino et al., 1984), or more prolonged
synaptic molecular adaptations, than experimentergiven stimulation or drug injections (Chen et al., 2008).
Placebo/nocebo effects are real in human studies, and the
expectancy of strong or uncertain drug effects are known
to affect human brain imaging results in response to
acute drugs (Volkow et al., 2010). For example, in
smokers, positive and negative beliefs on nicotine content
of cigarettes influenced functional magnetic resonance
imaging (fMRI)-scanned striatal responses to value and
reward prediction errors during an investment task (Gu
et al., 2015), indicating that beliefs can affect cognitive
performance also under the drug-associated states. These
issues indicate that, in addition to direct pharmacological
actions, abused drugs may also change basic learning and
memory processes, for example, by conditioning and
environmental factors.
A. Different Forms of Neuroplasticity
The ability of the brain to remodel its connections
functionally and structurally in response to individual
experience has been described by the concept of neuroplasticity. Neuroplasticity occurs on a variety of levels
ranging from molecular changes in synapses to largescale changes involved in neurocircuitry remapping.
Synaptic plasticity refers to adaptive changes in the
strength of synaptic connections. On the basis of its time
frame, synaptic plasticity has been classified as shortterm (acts on a timescale of milliseconds to minutes)
and long-term (hours to days) plasticity. Short-term
plasticity is achieved through transient changes, such
as facilitation or depression of a synaptic connection,
which then quickly return to their initial state. However, repeated stimulation causes a persistent change
in the connection to achieve long-term plasticity.
Hebbian or activity-dependent plasticity is the most
studied form of long-term plasticity. It occurs when
presynaptic stimulation coincides with postsynaptic
depolarization (Hebb, 1949; Bi and Poo, 2001). The
best-known example of Hebbian plasticity is N-methylD-aspartate receptor (NMDAR)-mediated long-term potentiation (LTP). Importantly, this form of LTP occurs
only in synapses that actively contribute to the induction process, so it is input and synapse specific. The
term anti-Hebbian plasticity currently describes

Drug-Induced Neuroplasticity

877

Fig. 1. Brain regions of major importance for the acute and chronic addictive effects of drugs of abuse. The top drawing shows many pathways that
participate in rewarding/drug-seeking behavior. The middle drawing depicts several pathways/brain regions that are particularly related to addictionrelated aversive behaviors (wide connections of the locus ceruleus to other brain areas are not shown). The bottom drawing illustrates the role of midbrainstriatal-cortical loops in goal-directed and habitual drug taking. See Fig. 10 for additional pathways involved in nicotine neurotoxicity. Amy, amygdala;
BNST, bed nucleus of stria terminalis; CeA, central nucleus of amygdala; DLS, dorsolateral striatum; DMS, dorsomedial striatum; HC, hippocampus; LC,
locus ceruleus; LDTg, laterodorsal tegmental nucleus; LH, lateral hypothalamus; LHb, lateral habenula; mPFC, medial prefrontal cortex; NAc, nucleus
accumbens; OFC, orbitofrontal cortex; rmTg, rostromedullary tegmental nucleus; SN, substantia nigra; VTA, ventral tegmental area.

either long-term depression (LTD) (Nelson, 2004) or LTP

that occurs when presynaptic activation coincides with
postsynaptic inactivity (Kullmann and Lamsa, 2007).
In rodents, the neuronal organization remains immature at birth (see below). The process that describes
changes in neuronal organization during development as a result of environmental interactions and
experience/learning-induced neural changes is known
as developmental plasticity. To maintain the balance
between neuronal excitation and inhibition, homeostatic plasticity regulates the overall activity of complex
circuits by specifically regulating the destabilizing

effects of developmental and learning processes. Otherwise, activity-dependent forms of plasticity could drive
neural activity toward runaway excitation or quiescence (Miller, 1996; Turrigiano, 1999; Turrigiano and
Nelson, 2004).
Metaplasticity refers to plasticity of synaptic plasticity, which describes changes in the ability to induce
further synaptic plasticity (Abraham and Bear, 1996).
For example, prolonged exposure to cocaine induces
a population of silent glutamatergic synapses in the
nucleus accumbens (NAc) that form sites for future
plasticity (reviewed in Lee and Dong, 2011).

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Korpi et al.

To help appreciate the effects of abused drugs on

synaptic plasticity, in the following paragraphs we will
briefly introduce mechanisms of the most common
presynaptic and postsynaptic forms of synaptic
plasticity.
B. Short-term Neuroplasticity
Short-term plasticity can appear as a transient facilitation, depression, or augmentation and posttetanic
potentiation in synaptic strength that lasts for up to
a few minutes (reviewed in Fioravante and Regehr,
2011). Despite the variety in synaptic neurotransmitters, all forms of short-term plasticity are primarily
governed by presynaptic mechanisms associated with
fluctuations of presynaptic residual Ca2+, which acts on
one or more molecular targets, resulting in the changes
in neurotransmitter release (Fig. 2). Enhancement of

Ca2+ channel activity and increases in the probability of

Ca2+ influx, altered vesicle pool properties, local depletion of Ca2+ buffers, and increases in quantal size of
neurotransmitter release contribute to short-term facilitation (Fioravante and Regehr, 2011). On the other
hand, vesicle depletion, inactivation of neurotransmitter release sites, and Ca2+ channels contribute to shortterm synaptic depression (Neher and Sakaba, 2008). In
addition, glial-neuronal interactions impact on shortterm synaptic plasticity by controlling the speed and
extent of neurotransmitter clearance from the synaptic
cleft (Bergles et al., 1999) as well as by astroglial release
of substances that can affect synaptic efficacy (Araque
et al., 2001). Most importantly, there is retrograde
communication between post- and presynaptic terminals: both endocannabinoids (reviewed in Wilson
and Nicoll, 2002; Kano et al., 2009) and nitric oxide

Fig. 2. Typical induction protocols and main factors regulating mechanisms of short-term plasticity. (A) Brief paired-pulse (PP) stimulation induces
short-term facilitation of neurotransmission by transiently increasing the Ca2+-dependent readily releasable pool (RRP) of synaptic vesicles. (B) Shortterm depression of neurotransmission can be induced by frequent tetanic stimulation, which transiently depletes synaptic vesicles. (C). Depolarizationinduced suppression of inhibition (DSI) or similarly that of excitation (DSE; not shown) is a locally induced transient depression of neurotransmission
that is dependent on retrograde eCB signaling. Depolarization-induced suppression of inhibition/excitation begins with stimulation of excitatory
neuronal connections inducing eCB synthesis, and 2-AG in particular then moves to activate presynaptic CB1 receptors on surrounding neurons. This
induces local, transient depression of inhibitory or excitatory (not shown) neurotransmission.

Drug-Induced Neuroplasticity

(NO)-guanylyl cyclase signaling (Sammut et al., 2010)

contribute in a general transient local process that
tunes neurotransmitter release and different aspects of
synaptic dynamics both in inhibitory and excitatory
synapses (discussed in more detail in sections II.G and
II.H). Short depolarization of a neuron may cause
a transient suppression of excitation or inhibition of
that and neighboring neurons, called depolarizationinduced suppression of excitation or inhibition (DSE

879

and DSI), which was found to be dependent on retrograde encocannabinoid (eCB) signaling (see section II.H
on cannabinoids).
C. Main Forms of Long-term Neuroplasticity:
Long-term Potentiation and Long-term Depression
Long-term forms of synaptic plasticity can appear as
potentiation (long-term potentiation, LTP) or depression (long-term depression, LTD) in synaptic strength

Fig. 3. Main factors regulating pre- and postsynaptic plasticity mechanisms, such as LTP and LTD, after most typical induction protocols. (A)
Presynaptic LTP is often measured using paired-pulse (PP) stimulation e.g., at 50-ms interstimulus intervals (ISI). This leads to presynaptic Ca2+
influx via VGCCs, activation of adenylate cyclase (AC) and phosphorylation of synaptic vesicular proteins, such as Rab3a and RIM1a, leading to
increased transmitter release. (B) During low-frequency stimulation (LFS; often used for LTD induction) weak presynaptic depolarization triggers only
a modest Ca2+ influx that activates phosphatases (calcineurin, protein phosphatase 1, and protein phosphatase 2) in the postsynaptic cell. These
phosphatases dephosphorylate AMPA and NMDA receptors, thus promoting receptor removal from the membrane. (C) During high-frequency
stimulation (HFS; often used for LTP induction) strong presynaptic depolarization triggers robust glutamate release promoting Ca2+ influx via AMPA
and NMDA receptors into the postsynaptic cell. This Ca2+ influx activates protein kinases (FYN, PKA, PKC, PKMz, and CaMKII) that phosphorylate
receptors and promote stabilization of receptors at the membrane. These kinases also activate local protein synthesis, which leads to insertion of new
receptors in the membrane. (D) By inducing robust glutamate release with HFS up to 300 Hz, activation of postsynaptic group I mGlu receptors leads
to AMPA receptor internalization. (E) The LTP that is dependent on retrograde endocannabinoid (eCB) signaling consists postsynaptic activation that
induces eCB synthesis, especially increasing 2-AG, which then acts presynaptically on CB1 receptors limiting transmitter release (for more details, see
Fig. 12). This form of plasticity can be experimentally evoked, e.g., in the striatal neurons by 100-Hz HFS.

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that last for hours to weeks. In contrast to short-term

plasticity, the nature of long-term forms of plasticity
involves both pre- and postsynaptic alterations (Fig. 3).
1. Presynaptic Forms of Long-term Plasticity.
Presynaptic LTP has been best studied at hippocampal
CA3 mossy fiber synapses (Weisskopf et al., 1994; Nicoll
and Schmitz, 2005), but similar forms of LTP have been
found in multiple brain areas (Salin et al., 1996; CastroAlamancos and Calcagnotto, 1999; Lopez de Armentia
and Sah, 2007). This presynaptic LTP appears at both
excitatory and inhibitory synapses and does not require
postsynaptic NMDARs (but see Yeckel et al., 1999).
Instead, presynaptic LTP appears to be induced by an
activity-dependent rise of presynaptic residual calcium
that results in a rise in cAMP and subsequent activation
of protein kinase A (PKA). This, in turn, modifies the
functions of proteins that act to coordinate synaptic
vesicle interactions with the presynaptic active zone,
leading to a long-lasting increase in neurotransmitter
release (Castillo, 2012).
Endocannabinoid-mediated long-term depression
(eCB-LTD) is a widely expressed form of long-term
plasticity at both excitatory and inhibitory synapses.
Brief robust neuronal stimulation triggers the synthesis
of eCBs, lipophilic molecules that travel retrogradely
across the synapse to activate the presynaptic CB1
cannabinoid receptors (see section II.H), which suppresses neurotransmitter release via a wide range of
effector molecules, including voltage-dependent calcium channels (VGCC), potassium channels, PKA, p38
mitogen-activated protein kinase (MAPK), and c-Jun
N-terminal kinases (JNK) (reviewed in Howlett et al.,
2002). Importantly, CB1 receptors activation per se is
not sufficient for eCB-LTD induction. Rather, the presynaptic terminal integrates multiple signals to generate eCB-LTD (Heifets and Castillo, 2009). CB1 receptors
also mediate short-term plasticity of DSI and DSE (Fig.
2). Interestingly, some hippocampal inhibitory synapses can undergo both short- and long-term forms of eCBmediated plasticity, where the time frame of depression
(short-term versus long-term manner) depends on the
downstream signaling pathways (Heifets and Castillo,
2009). Particularly, cAMP/PKA-dependent signaling
has been shown to be necessary only for eCB-LTD but
not for DSI (Chevaleyre and Castillo, 2003).
2. Postsynaptic Forms of Long-term Plasticity.
NMDAR-dependent LTP and LTD are the best understood forms of long-lasting synaptic plasticity (Bliss
and Lomo, 1973; Hayashi et al., 2000). Early phases of
LTP and LTD are mediated by a redistribution of both
a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
receptors (AMPAR) and NMDARs at the postsynaptic
membrane and/or by changes in presynaptic transmitter release. With time, such changes are consolidated by
structural alterations, which require synthesis of new
proteins (Kasai et al., 2010).

In in vitro experiments on acute brain slices, LTP and

LTD can be induced by distinct patterns of activity
(reviewed in Holscher, 1999; Luscher and Malenka,
2012) (Fig. 3). High-frequency stimulation (HFS) of the
presynaptic cell (tetanic pulses at 50100 Hz) is commonly used to induce LTP. This stimulation protocol
causes a strong postsynaptic depolarization that removes
the Mg2+ block of NMDARs, allowing timed Ca2+ influx.
This triggers the downstream molecular cascades inducing LTP. In contrast, low-frequency stimulation (LFS,
at 0.15 Hz) often induces LTD. Typically, it causes only
a weak postsynaptic depolarization that results in a modest but prolonged Ca2+ influx triggering the downstream
molecular cascades driving to LTD.
Since the original discovery of LTP in the hippocampus (HC) (Bliss and Lomo, 1973), LTP and LTD have
been observed in a variety of other brain regions
including the ventral tegmental area (VTA), NAc,
PFC, and amygdala ex vivo (Luscher and Malenka,
2011) and in vivo (Canals et al., 2009; Zhang et al.,
2015b). Different brain regions appear to exhibit different forms of LTP and LTD, and therefore, synapses
recruit different signaling pathways to accomplish their
functions. The most studied forms of neuroplasticity are
NMDAR-dependent LTP and LTD, with the NMDARs
providing the major pathway for Ca2+ influx (Huang
and Kandel, 1996). There is also NMDAR-independent
LTP and LTD, in which VGCC (Kato et al., 2009) or
GluA2 subunit-lacking AMPARs (Lamsa et al., 2007)
provide the Ca2+ influx triggering induction.
In the early phases of LTP, elevated Ca2+ triggers
persistent activation of protein kinases including PKA,
Ca2+/calmodulin kinase II (CaMKII), and protein kinase C (PKC). A striking feature of CaMKIIa is its
capacity for autophosphorylation at threonine residue
Thr286, which keeps this kinase activated even in the
absence of Ca2+ (Giese et al., 1998). During this stage,
atypical protein kinase C (PKMz) may also become
autonomously active (Ling et al., 2006; Sacktor, 2008).
Autonomously active and other protein kinases use
phosphorylation to carry out the two major mechanisms
underlying the expression of LTP: first, they phosphorylate existing AMPARs and NMDARs to increase their
activity, and second, they mediate the insertion of new
receptors into the postsynaptic membrane (see below for
more detailed description).
3. a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid and N-methyl-D-aspartate Receptor Phosphorylation.
Huganir and coworkers made detailed experiments
on the regulation of AMPAR trafficking and function
by phosphorylation during LTP/LTD (reviewed in
Shepherd and Huganir, 2007). During LTP, PKA and
CaMKII are recruited to phosphorylate serine residues
in the GluA1 subunit at Ser831 (Mammen et al., 1997)
and Ser845 (Roche et al., 1996) and the GluA2 subunit
at Ser880 (Chung et al., 2000), promoting receptor
insertion and synaptic potentiation (Malenka and Bear,

Drug-Induced Neuroplasticity

2004; Huganir and Nicoll, 2013). Inhibition of PKA and

CaMKII or removal of the above-mentioned phosphorylation sites from AMPAR subunits can impair LTP
(Lee et al., 2003; Malenka and Bear, 2004). Importantly,
knock-in mutant mice that lack both Ser831 and Ser845
phosphorylation sites on GluA1 subunits demonstrated
impaired memory in behavioral tests (Olivito et al.,
2014).
Conversely, during LTD, phosphatases calcineurin
and protein phosphatases 1 and 2 are recruited to
dephosphorylate AMPARs, promoting their removal
from the synapse (Malenka and Bear, 2004; Huganir
and Nicoll, 2013).
Phosphorylation of NMDARs is also essential during
LTP/LTD expression because it contributes to stabilization of the receptors at the synapse by forming more
stable binding to postsynaptic density (PSD) proteins.
In fact, Fyn and Src kinases phosphorylate GluN2B
subunit at Tyr1472, which prevents the clathrin adaptor protein AP-2 from binding to the GluN2B subunit,
thus blocking endocytosis (Zhang et al., 2008).
4. a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid and N-methyl-D-aspartate Receptor Trafficking.
During LTP, new GluA2 subunit-lacking AMPARs are
rapidly transported to the cell surface under the influence of protein kinases (Malinow and Malenka, 2002;
Luscher and Malenka, 2012). Importantly, these new
AMPARs exhibit some unique properties: first, they
have greater single-channel conductance and, second,
greater permeability to Ca2+ ions, which facilitates
Ca2+-dependent signaling events. Noteworthy, this
early insertion of new Ca2+-permeable non-GluA2containing AMPARs to the synapse is independent of
protein synthesis. This is achieved by having a nonsynaptic pool of AMPARs adjacent to the postsynaptic
membrane (Kauer and Malenka, 2007). Moreover,
NMDARs are also actively replaced during LTP/LTD
(Barria and Malinow, 2002). However, the data on
NMDARs are still puzzling due to wide variability in
expression, kinetics, and regulation sites (reviewed in
Shipton and Paulsen, 2014). Particularly interesting for
LTP expression are the GluN2B subunit-containing
NMDARs because of their special association with CaMKII. This interaction maintains CaMKII close to its
substrates, such as AMPARs, to initiate the phosphorylation events that support synaptic strengthening.
Postsynaptic LTD is associated with receptor withdrawal from the synapses (Hayashi et al., 2000; Bellone
and Luscher, 2006). LTD can also be generated by
activation of VGCCs (Christie et al., 1997) or metabotropic glutamate receptors (mGlu) (Bellone and Luscher,
2006) and does not require NMDAR activation. Although
the above cellular model of LTP/LTD presented above is
explained entirely by its postsynaptic mechanisms, additional events may also occur presynaptically, for example,
via alteration in probability of glutamate vesicle release

881

by different retrograde signaling mechanisms (reviewed

in Luscher and Malenka, 2012).
With time, the insertion/removal of additional receptors is likely to result in the rearrangement of the PSD
with different scaffolding proteins, spine ultrastructure, or even spine density that requires gene transcription and protein synthesis. In fact, spines associated
with synapses that underwent LTP were found to
be enlarged (Matsuzaki et al., 2004; Holtmaat and
Svoboda, 2009; Kasai et al., 2010), whereas spines that
underwent LTD were shrunken or even disappeared
(Nagerl et al., 2004; Kasai et al., 2010). Although these
structural changes are not absolutely required for
neuroplasticity, the stabilization and maintenance of
existing synapses needs activity of several kinases such
as PKA, CaMKIV, PKMz, and ERK that induce protein
synthesis either locally in the dendrites from prefabricated mRNAs or by nuclear transcription (Sacktor,
2008). These mechanisms are also involved in synaptic
tagging, an activity-driven molecular labeling of synapses to be strengthened (Frey and Morris, 1997; Sajikumar
and Frey, 2004; Sajikumar and Korte, 2011).
D. Forms of Long-term Plasticity at
Inhibitory Synapses
Several forms of NMDA receptor-dependent neuroplasticity (both LTP and LTD) have been described at
inhibitory GABAergic synapses (reviewed in Castillo
et al., 2011). Depending on interneuron subtype and
brain region, inhibitory synaptic plasticity results in
changes either in presynaptic GABA release or in
postsynaptic g-aminobutyric acid A (GABAA) receptor
responsiveness. Interneurons also show glutamatergic
synapse plasticity, which has characteristics that are
partly different from those of principal neurons
(reviewed in Kullmann and Lamsa, 2011).
Presynaptic inhibitory plasticity is mediated via retrograde messengers produced in an activity-dependent
manner (by afferent stimulation of excitatory inputs) in
the postsynaptic neuron and transferred back across the
synapse to modulate presynaptic GABA release. The most
studied presynaptic form of the plasticity is the eCBmediated inhibitory LTD, in which released eCBs inhibit
presynaptic GABA release by acting on CB1 cannabinoid
receptors (Chevaleyre et al., 2006; Adermark et al., 2009)
(Fig. 3). Another form of inhibitory plasticity, NOmediated inhibitory LTP, requires NO as a retrograde
messenger to stimulate presynaptic guanylyl cyclase,
resulting in the potentiation of presynaptic GABA release
(Nugent and Kauer, 2008). Brain-derived neurotrophic
factor (BDNF)-tropomyosin receptor kinase B (TrkB)mediated inhibitory LTP recruits BDNF that activates
its presynaptic receptor TrkB and potentiates GABA
release (Xu et al., 2010). It is evident that GABAergic
synapses from interneuron populations are very plastic
and actively participate in brain circuit refinement, learning, and memory formation (Chen et al., 2015).

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Postsynaptic inhibitory plasticity is also mediated by

diverse mechanisms in different synapses. Similar to
glutamatergic receptors, phosphorylation of postsynaptic GABAA receptors by protein kinases, including PKA,
PKC, CaMKII, and Src, leads to changes in the integral
anion channel function (reviewed in Nakamura et al.,
2015). The effects of phosphorylation are dynamic
(increases and decreases in receptor activity) and dependent on the subunit composition of the GABAA
receptor in a fashion that is not fully known at present.
Moreover, phosphorylation of cation-chloride cotransporters such as Na+-Cl2 cotransporters, Na+-K+-2Cl2
cotransporters, and K+-Cl2 cotransporters (KCCs)
affects their activity and consequently the amplitude
of GABAA receptor-mediated responses by altering the
transmembrane anion gradients (reviewed in Kaila
et al., 2014). The function of GABAA receptors is further
dynamically regulated by constitutive exo- and endocytosis of receptors at GABAergic synapses (reviewed in
Michels and Moss, 2007).
E. Developmental Maturation of the Brain in Rodents
and Humans
Brain development is a delicate and complicated process
that can be adversely affected by drugs during pregnancy,
leading to teratogenic effects (reviewed in Manent et al.,
2008; Jutras-Aswad et al., 2009; Holbrook and Rayburn,
2014; Ross et al., 2015). In the present review, there will be
only short notes on drug actions on fetal brain development, such as fetal alcohol effects during pregnancy or
early postnatal period in rodents (Valenzuela et al., 2012).
A thorough comparative analysis of early brain maturation in different species, including rodents and human,
recently appeared (Workman et al., 2013). It is possible
that vulnerability for drug abuse may be greater the
younger the exposure/use of drugs is started.
Developmental neuroplasticity is based on genetic
programs in addition to activity-dependent processes,
and after the maturation, the neuroplasticity is expected
to be more homeostatic, dependent on molecular interactions in brain cells, neurites, spines, and synapses
within a relatively rigid extracellular milieu. The relevant question to the review of drug-induced neuroplasticity is the vulnerability of the brain to drug effects
during periods of childhood, adolescence, and adulthood.
These periods are often defined in humans as adolescence, starting at 10 to 12 years of age and ending at 18 to
20 years. Childhood precedes it and adulthood comes
after it, and these periods can be further subdivided into
shorter periods by using behavioral and brain maturation
indexes (Bossong and Niesink, 2010; Pressler and Auvin,
2013; Semple et al., 2013). For the present review an
important aspect to consider is how rodent models at
specific postnatal ages compare with human childhood,
adolescence, and adulthood. Figure 4 gives a rough
estimation of how to relate differently timed rodent
experiments to human brain developmental stages. The

Fig. 4. Phases of brain development and comparable ages in humans and

rodents (modified from Semple et al., 2013 and Flurkey and Currer, 2004).
(A) Number of spines (per 50 mm of the apical dendrite) of the human
prefrontal cortical pyramidal neurons in layers IIIc and V are shown by
curves estimated from (Petanjek et al., 2011). The figure illustrates normal
behavioral features (in boxes) and the onsets of attention deficit
hyperactivity disorder (ADHD) and schizophrenia. It is important to note
that puberty in female rats takes place roughly from P28 (vaginal opening)
to the first estrus cycle on P40 and in male rats from P40 (balanopreputial
separation) to spermatozoa maturation on P60, respectively (Schneider,
2008). (B) Postnatal development of the number of neurons (yellow traces)
and nonneuronal cells (blue) for whole rat brain (WB), cerebral cortex (Ctx,
with the scale in parentheses), and cerebellum (Cb) (Bandeira et al., 2009;
Mortera and Herculano-Houzel, 2012) indicates rapid changes in rodents
during the first 3 postnatal weeks, the cell numbers remaining rather
stable after that. (C) Timelines for the brain developmental processes
important for the functions of neuronal and various glial cells.

figure depicts various brain cell developmental processes,

emergence of selective behavioral phenotypes, and the
development of the behavioral modulation of brain processes by external stimuli in humans and rodents.
Several precautions have to be kept in mind, though.
First, there is a large variation between the developmental program timescale for different brain regions,
with the cortical regions and the cerebellum developing
last (Huttenlocher, 1979; 1990; Huttenlocher and
Dabholkar, 1997). Second, there are genetic, sex, and
disease vulnerability differences between the phases of
brain development (Thompson et al., 2001; Vasileiadis
et al., 2009; Asato et al., 2010; Brenhouse and Andersen,
2011; Dennis and Thompson, 2013). Third, various
neurotransmitter systems develop at different timelines

Drug-Induced Neuroplasticity

in different brain regions, with the DAergic and

GABAergic systems of the cortex developing late (Tseng
et al., 2007; Hashimoto et al., 2009; Kilb, 2012; Manitt
et al., 2013; Ouellet and de Villers-Sidani, 2014). Fourth,
various neurotrophic factors and their receptors have
differential expression profiles in various brain regions
(Perovic et al., 2013). Thus, the prolonged effects of
drugs of abuse are also dependent on the developmental
time of the exposure to drugs (Stanwood and Levitt,
2004). Furthermore, activating and stress-relieving
effects including neonatal handling, maternal care,
juvenile play, enriched environment, social contacts or
lack thereof, and lesioning effects on the brain also have
long-term effects and their critical times (Meaney et al.,
1988; Liu et al., 1997; Caldji et al., 1998; Bouwmeester
et al., 2002; Sale et al., 2007; Tseng et al., 2009; Foscarin
et al., 2012). A good example is the differential activation of the caudate-putamen, NAc, and PFC of rats at
different ages by a stress-inducing dose of the GABAA
receptor benzodiazepine-site inverse agonist FG-7142
(Lyss et al., 1999) known to induce a stress-like activation
of the mesocortical DA system in adult rats. The DA
system has a delayed maturation in the cortex, becoming
mature by postnatal day 60 (Kalsbeek et al., 1988). At
postnatal day 10, only the NAc is strongly activated by
FG-7142, at day 18 all regions start to be activated, and
finally at 45 and 100 days of age, the PFC is the brain
region that is activated the most.
Potential for neuroplasticity is greater in young than
adult rodents (Hensch, 2005; Bavelier et al., 2010;
Hensch and Bilimoria, 2012), as is demonstrated, for
example, by easier induction of the NMDAR-dependent
LTP using tetanic stimulation in the NAc neurons of
3-week-old than adult mice (Schramm et al., 2002).
Furthermore, the brain growth-promoting and limiting
responses to injury are blunted and dysregulated in
elderly (2224 months) versus adult (24 months) rats
(Li and Carmichael, 2006; Li et al., 2010b).
Perhaps an extreme illustration of the prolonged
neurodevelopmental process and normal potential for
neuroplasticity in humans may be the profiles of layer
IIIc and V spine densities in normal PFC (Petanjek
et al., 2011), which is illustrated in Fig. 4A. The spine
densities were determined using Golgi staining of postmortem brain sections at various ages. The peak density
of dendritic spines is seen at the age of 512 years, after
which the density slowly reduces to stable levels after
30 years of age. This extended spine-pruning period is
consistent with the results of human functional magnetic resonance imaging and connectivity studies that
have indicated prolonged developmental changes in the
cortical areas (Thompson et al., 2005; Knickmeyer et al.,
2008; Dosenbach et al., 2010). A corresponding delayed
development of the structural connectivity between basolateral amygdala and mPFC has been observed in the rat
(Cunningham et al., 2002), with a wide range of different
experiences, including the effects of various drugs of abuse,

883

known to induce long-lasting plasticity in the PFC also in the

adulthood (Kolb and Gibb, 2015).
F. Developmental Neuroplasticity: Critical Periods,
Reopening of Plasticity in Adults
The development and critical period plasticity of the
sensory systems, particularly the visual cortex, have been
well described. In rats and mice, critical periods of
plasticity in the visual, somatosensory barrel, and auditory
cortices take place early in the development of these
sensory systems. Importantly, some of the associated
plasticity mechanisms are reused or reopened in adult
neuronal plasticity. Drugs inhibiting or stimulating the
GABAA receptors can promote or delay the critical periods,
respectively (Hensch, 2005). Synaptic pruning eliminates
extra nonfunctional connections formed during initial
overproduction of synaptic connections, while strengthening functionally important ones (Changeux and Danchin,
1976). In the normal adult brain, neural plasticity is
needed for maintaining neuronal network excitability,
large-scale regulation of cortical and subcortical circuits,
and fine-scale experience-dependent refinement and
maintenance of local circuits (Griffen et al., 2012).
The extracellular matrix (ECM) network is an active
participant in brain function and neuroplasticity
(reviewed in Pavlov et al., 2004). The ECM consists of
various molecules (glycoproteins and proteoglycans)
secreted by all cells that are assembled inside this
matrix (Bosman and Stamenkovic, 2003). ECM network
regulates synaptogenesis, consolidation, strengthening,
and maintenance of synapses (Fields and Itoh, 1996).
During development, ECM participates in neuronal
differentiation, neuronal movement, guidance for growing axons, and synaptogenesis (Pavlov et al., 2004). In
the mature brain, ECM is crucial not only for anchoring
of neurons and organization of brain regions (structural
function) but also for transducing a wide range of
signals to the neurons (Thalhammer and Cingolani,
2014). Interaction between the ECM and cell is facilitated by cell adhesion molecules (CAMs), particularly
by integrins. Integrins are heterodimeric transmembrane glycoprotein receptors that mediate ECM-cell
interactions via binding ECM proteins and cellular
transmembrane proteins (e.g., ion channels and growth
factor receptors). ECM plays an important role in
regulating actin polymerization, spine morphology,
and GluA2 subunit trafficking in culture (Wu and
Reddy, 2012). In regard to this review, suppression of
the synthesis of integrin-linked kinase increases the
level of Ser845 phosphorylated GluA1 subunitcontaining receptors and spine density in the NAc and
blocks cocaine-induced sensitization (Chen et al., 2010).
Moreover, disruption of integrin expression in the NAc
interfered with trafficking of GluA2 subunit-containing
receptors, which affected cocaine-induced conditioned
place preference (CPP) and reinstated drug seeking
(Wiggins et al., 2011).

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Perineuronal nets (PPN), first described by Camillo

Golgi (reviewed in Celio et al., 1998), develop around
specific neuronal populations to protect highly active
neurons and to preserve their structure in an
experience-dependent manner during pruning of extra
connections in the visual cortex and many other parts of
the central nervous system (CNS) (Kwok et al., 2011;
Soleman et al., 2013; Ye and Miao, 2013). PNNs are
primarily composed of chondroitin sulfate proteoglycans (e.g., aggrecan, versican, neurocan, brevican, and
phosphacan), hyaluronan, link proteins such as cartilage
link protein 1 Crtl1 or Hapln1 (Carulli et al., 2010), and
tenascins. In the cortex, PNNs selectively surround the
parvalbumin (Pv)-containing fast-spiking GABAergic
interneurons (Ye and Miao, 2013), starting after postnatal day 10 (P10) and achieving adult levels by P42.
Thus, the PNNs develop during the critical period, and
after closing, the critical period for plasticity can be
reopened by degradation of the PNNs (Pizzorusso et al.,
2002). Although the negatively charged components of the
PNN can have multiple molecular interactions and functions, for the maturation of Pv-interneurons and regulation of critical periods, the PNN provides a high-affinity
binding site for the lysine-arginine containing domain of
the transcription factor Otx2 (orthodenticle homeobox 2)
(Beurdeley et al., 2012). Once Otx2 reaches the Pvinterneurons of the visual cortex, being synthesized in
the retina or the lateral geniculate of the visual tract
(Sugiyama et al., 2008), it induces expression of Pv, GAD65
(glutamate decarboxylase 65 kDa), GABAA a1 subunit,
and Kv3.1b K+ channels specifically in these target
neurons (Sugiyama et al., 2008). This process is experience
dependent, that is it cannot begin before eye opening, after
which the critical period for setting ocular dominance and
visual acuity is started (Fagiolini and Hensch, 2000;
Sugiyama et al., 2009). Pv-interneurons in the visual
cortex mature in connections (e.g., forming perisomatic
synapses on principal neurons) and intrinsic firing properties (e.g., fast spiking) by the end of the critical period,
thus allowing the firm functional cortical connections for
binocular visual acuity to be formed (Kuhlman et al.,
2010). PNNs interact with receptors such as NgR1 (NoGo
receptor) and leukocyte common antigene-related phosphatase (Akbik et al., 2013; Ye and Miao, 2013).
PNN formation in the basolateral amygdala (BLA)
stabilizes fear memories in adults, unlike in the developing
brain when they can be readily extinguished (Gogolla
et al., 2009). Degradation of PNN by the enzyme chondroitinase ABC in the BLA, left the fear conditioning
intact, but after extinction the animals failed to spontaneously recover the fear and to express freezing under the
fear-related context, indicating erasure of the memory by
degradation of the PNN. Two recent papers indicate that
PNNs affect drug- and experience-induced memory in
rodents. First, Karpova et al. (2011) showed that fluoxetine
treatment during extinction training in fear-conditioned
adult mice led to erasure of fear memory, associated with

a reduction in the proportion of Pv-containing interneurons with PNN expression in the BLA, HC, and infralimbic
cortex (IL). In the BLA, fluoxetine treatment also increased the expression of polysialynated neuronal cell
adhesion molecule (PSA-NCAM) and decreased KCC2
levels in the BLA and HC, with all these data suggesting
that fluoxetine treatment with extinction training induced
a juvenile-like state in the interneurons of the fear
circuitry. Second, infusions of chondroitinase ABC into
the BLA or the central nucleus of the amygdala (CeA) of
adult rats during extinction of morphine- and cocaineinduced CPP prevented priming-induced reinstatement
(Xue et al., 2014). This effect was associated with increased
levels of AMPAR GluA1 and GluA2, but not GluA3, and
increased BDNF levels in the BLA. Thus, the extracellular
matrix and its restructuring seem to be involved in the
modulation of specific memories that can also be associated with persistent drug effects. Perhaps, changes in the
matrix may be developed into future therapies for enhancing or reversing plasticity (Castren et al., 2012). However,
we should learn more about how the extracellular matrix
induces or restricts plasticity and when would be the right
time to increase or decrease the matrix components in
appropriate neuronal circuits.
One of the major anionic extracellular components
around mature interneurons is formed by PSA-NCAM
molecules with antiadhesive properties. Expression of
PSA-NCAM has been described in a subpopulation of
GABAergic calbindin-positive and somatostatinpositive neurons in the adult rat and mouse cerebral
cortex, without expression in the principal neurons or
other interneuron types (Gomez-Climent et al., 2011).
These PSA-NCAM-positive interneurons had reduced
synaptic connections as judged from confocal immunohistochemical counting of synaptophysin-positive perisomatic and peridendritic puncta in close apposition to
GAD67-expressing cells. This suggests that expression
of PSA restricts the synaptic connections of the interneurons in mature brain. Interestingly, DAergic agonists increase (Castillo-Gomez et al., 2008) and also
serotonergic drugs increase (or downregulate stresselevated) (Wedzony et al., 2013) production of PSA in
the mPFC. NCAM is needed for hippocampal LTP that
is deficient in NCAM-KO mice (Caroni et al., 2012;
Stoenica et al., 2006). Intraventral mPFC infusion of
endoneuraminidase, which cleaves PSA from NCAM to
mice that were trained to extinguish operant alcoholseeking behavior, strongly attenuated extinction (Barker
et al., 2012), suggesting that reduced levels of PSANCAM restricts the plasticity needed for extinction.
Similarly to PNNs, extracellular NCAM and PSANCAM mechanisms also participate in retaining the
mature structures, although they are also needed for
novel connections and pathways of plasticity. They do
offer a number of possible, but still deficiently characterized, targets for drug action, and they may be important
for understanding impairments of interneuron function

Drug-Induced Neuroplasticity

in depression and schizophrenia (Nacher et al., 2013;

Wedzony et al., 2013).
G. Neurotrophins as Regulators of Neuroplasticity:
Brain-Derived Neurotrophic Factor as an Example
BDNF is an important trophic factor for nerve cells in
the CNS (Park and Poo, 2013), and it serves here as an
example of the multiple roles that the neurotrophins are
playing in orchestrating development, maintenance,
and plasticity of neurogenesis and neural connections.
It is secreted from various cells activity dependently
and exerts effects on local synaptic plasticity.
In short, mature BDNF is a 14-kDa protein that is
cleaved from prepro-BDNF expressed both in neurons
and glial cells in the CNS. BDNF gene has IX promoters
in humans and rodents, and at least the promoter IV is
activity dependent with Ca2+ and cAMP response
elements (Park and Poo, 2013). BDNF preferentially
acts via activation of tropomyosin receptor kinase B
(TrkB) (Minichiello, 2009). Like many of the trophic
factor receptors, TrkB belongs to the family of receptor
tyrosine kinases. Signaling of BDNF via TrkB leads to
activation of Ras-ERK, phosphatidyl inositol 3-kinase
(PI3K) and phospholipase C, gamma (PLCg) pathways,
which serve for survival, differentiation, and synaptic
plasticity phenomena in neurons (Minichiello, 2009).
Pro-BDNF activates preferentially P75 neurotrophin
receptor and often has opposite or different effects than
mature BDNF (Lu et al., 2005).
BDNF has important interactions with the GABA
system. It is needed for the GABA system to become
inhibitory during development (Huang et al., 1999), but
its activation in the mature nervous system may lead to
reduction of KCC2 expression and subsequent change to
GABAergic excitation. This has been described during
development of neuropathic pain in the spinal cord, with
activated microglial cells releasing BDNF, which makes
the circuitry abnormally sensitive to stimuli due to
downregulation of KCC2 expression (Coull et al., 2005)
and due to LTP induction via GluN2B upregulation
(Ding et al., 2014). In similar preclinical models, certain
benzodiazepine-site agonists, the efficacy of which is
supposed to be dependent on KCC2-driven Cl2 gradients, surprisingly show strong analgesic effects by
ablating neuropathic pain symptoms (Knabl et al.,
2008; Paul et al., 2014a), stressing that multiple parallel
pathways are involved (Zeilhofer et al., 2012). The KCC2
downregulation and GABAergic excitation also appear to
switch rewarding responses in the CPP test to intra-VTA
GABAA agonist muscimol from DA-sensitive to DAinsensitive (or vice versa for the antagonist bicuculline)
in opioid-dependent rats (Laviolette et al., 2004). This
condition could be mimicked by intra-VTA infusion of
BDNF (Vargas-Perez et al., 2009). Furthermore, more
recently it was shown that in stressed animals, specific
hypothalamic neurons are excited by GABA due to stressinduced phosphorylation and endocytosis of KCC2

885

(Sarkar et al., 2011). These striking results appear to

link chronic drug exposure, stress, and aversive pain
stimuli to pathologic neuroadaptation in BDNF and
GABA systems and indicate that boosting the chloride
gradients might be an attractive drug development
target (Gagnon et al., 2013).
Although GABAA receptor-mediated excitation or
depolarization in principal neurons is known to be
important in early neuronal development (Ben-Ari
et al., 2007; Blaesse et al., 2009) and perhaps in specific
pathologic conditions in the mature nervous system
(Medina et al., 2014), to our knowledge there is still
little evidence that drugs acting on GABAA receptors
would induce tolerance via reversed Cl2 gradients
during in vivo treatments. In addition, acute behavioral
effects of drugs with preferential action on extrasynaptic GABAA receptors, including gaboxadol, were not
affected in mice hypomorphic to KCC2, although the
responses to the synaptic GABAA receptor agonist
diazepam were strongly blunted (Tornberg et al.,
2007). Interneurons express KCC2 already early in
development (Batista-Brito et al., 2008), consistent with
shunting inhibition in the interneurons already at
postnatal days ,10 (Banke and McBain, 2006). The
stabilized role of specific interneuron populations, such
as Pv-interneurons, may become even more important
at the end of the critical periods (Hensch, 2014).
7,8-Dihydroxyflavone, a specific small molecule agonist of TrkB receptors, has a wide activity in various
preclinical tests for cognitive and emotional behaviors
(Baker-Andresen et al., 2013), but to our knowledge, it
has not yet been tested for modulation of drug-induced
plasticity. Perhaps only together with a systemically
active antagonist of TrkB receptors, the roles of BDNFTrkB signaling in various phases of drug-induced
plasticity would become better established. However,
as mentioned above, in the developing CNS during the
critical periods of cortical circuitry formation BDNF
signaling is indispensable for maturation of GABAergic
inhibition (Huang et al., 1999) (reviewed in Kuczewski
et al., 2010).
As discussed above, inhibitory interneurons have an
important role in neuroplasticity, and their diversity,
development, and functions were recently characterized
in the cortical regions (Klausberger and Somogyi, 2008;
Ascoli et al., 2008; Lapray et al., 2012), but only initially
in the midbrain (Olson and Nestler, 2007; Nair-Roberts
et al., 2008). Because the midbrain GABAergic interneurons even have different embryonic origins to the
cortical interneurons, likely subpopulations and characteristics of midbrain interneurons will be an interesting target for research and drug effects.
H. Animal Models of Drug Reinforcement
and Addiction
Animal models are critical for understanding the
neurobiological basis of drug actions and drug addiction.

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Because addiction is a human phenomenon, there are

no complete animal models for it. However, some
characteristics of this syndrome can be satisfactorily
modeled in laboratory animals. It is generally agreed
that when viewed as experimental preparations for
studying the human syndrome, animal models exhibit
good construct and predictive validity, even if their face
validity can be disputed (for a comprehensive review,
see Sanchis-Segura and Spanagel, 2006).
Conceptualizations of the development of addiction hold
that drugs are initially taken voluntarily because of their
positive reinforcing or rewarding effects, and therefore
models have been constructed for evaluating the ability of
drugs to act as reinforcers or conditioned reinforcers,
including a variety of animal models of drug SA. Behaviorally, they can be classified as operant models based on
operant conditioning and nonoperant models that are
restricted to various oral SA procedures used particularly
for measuring ethanol consumption. Traditionally, these
models were based on a two-bottle choice between water
and ethanol solution, but it was subsequently found that
manipulation of the temporal access to ethanol can
increase the consumed ethanol during drinking bouts,
leading to development of binge-drinking models (Wise,
1973; Rhodes et al., 2005; Simms et al., 2008).
Operant models are based on the delivery of a reinforcer
contingently to the completion of the required response
that is determined by the reinforcement schedule. Reinforcement schedules exert powerful control over behavior and can be used for evaluating the nonspecific and
motivational drug effects. For example, progressive ratio
schedules can measure the reinforcing efficacy of a drug,
whereas the second-order schedules are useful for studying the role of conditioned reinforcers in maintaining
behavior. Various routes of SA can be used, e.g., intravenous, intracranial, intragastric, or oral. In particular, the intravenous drug SA animal model is considered
to be predictive of drug abuse potential in humans.
In conditioned preference paradigms, drugs effects (unconditioned stimulus) are paired repeatedly with a previous neutral stimulus. Through Pavlovian conditioning,
the neutral stimulus acquires the ability to act as a conditioned stimulus. Most commonly, conditioned preference is
studied using CPP procedures. These procedures use an
apparatus with two or more separate distinctive compartments. Access to one compartment is paired with drug
injections, whereas the other compartment is accessible
after vehicle injections. After repeated pairings of the drug
and the vehicle with their compartments, the animal is
allowed to move freely in all compartments during the test
session. Increase in the time spent in the drug-associated
compartment is taken as a measure of CPP.
Animals will perform tasks to self-administer electrical trains of stimulation to many different brain
areas, particularly along the medial forebrain bundle,
leading to the idea that direct activation of brain reveals
the circuitry involved in reinforcement from natural

rewards. Various intracranial self-stimulation (ICSS)

procedures have been used for mapping the neural
circuitry mediating drug reinforcement and pharmacological suppression thereof. Many abused drugs acutely
decrease the ICSS reward threshold, whereas increased
thresholds have been seen during withdrawal after
induction of dependence.
Compulsive drug seeking and relapse to drug use are
considered to be the hallmarks of addiction, and
therefore attempts have been made to model these
aspects of addiction in animal models. Particularly for
modeling drug-seeking behavior, reinstatement procedures are now being commonly used. These procedures
consist of the initial phase of operant drug SA, the
extinction phase during which operant responses have
no programmable consequences, and the reinstatement
phase during which the extinguished responding is
reinstated either with a priming dose of the drug,
conditioned stimuli associated with the drug, stressful
footshocks, or pharmacological stressors. Drug seeking
induced by re-exposure to drug-associated cues has
been shown to progressively increase over several
weeks after withdrawal from drug SA, a phenomenon
that has been called incubation of drug craving (Lu
et al., 2004), which is reminiscent of the alcohol
deprivation effect found earlier in rats after a period of
abstinence (Sinclair, 1972). The compulsive features of
drug taking, such as resistance to adverse consequences
and escalated intake, are accentuated in models in which
the daily access to a drug is extended (Ahmed and Koob,
1998; Deroche-Gamonet et al., 2004; Vanderschuren and
Everitt, 2004).
Psychomotor or behavioral sensitization refers to the
progressive increase in locomotion when abused drugs
are administered repeatedly. This phenomenon is in
essence nonassociative, but the context of drug administration has been demonstrated to have a role in the
induction and expression of sensitization. It has been
theorized that psychomotor sensitization also entails
increased incentive salience of stimuli associated with
drug effects, and therefore sensitization is implicated in
transition to compulsive drug seeking and taking
(Robinson and Berridge, 1993).
II. Actions and Persistent Effects of Specific
Drugs of Abuse
A. Cocaine, a Stimulant and Local Anesthetic
Cocaine, derived from the leaves of the coca plant, is
a very potent psychostimulant. Cocaine and its derivatives, can be inhaled, injected into the bloodstream, or
smoked, with the duration and intensity of effects
depending on the route of administration. Its effects
include euphoria (which might eventually be replaced
by anxiety), hyperactiveness, suppression of appetite,
local anesthesia, and possible sudden death due
to cardiac arrest that makes it considerably more

Drug-Induced Neuroplasticity

dangerous than other psychostimulants (for comprehensive review, see Grabowski, 1984). In addition,
cocaine has been associated with a variety of cardiovascular disorders, including myocardial infarction, heart
failure, cardiomyopathies, arrhythmias, aortic dissection, and endocarditis (Schwartz et al., 2010).
Cocaine is a DA, norepinephrine (NE), and serotonin
reuptake inhibitor (Fig. 5; Table 1). It also blocks
voltage-dependent sodium channels, which produces
local anesthesia, and also has been shown to cause
locomotor depression rather than stimulation (Reith
et al., 1985). Cocaine increases plasma catecholamine
levels; therefore, it exhibits sympathomimetic properties. As a consequence, it is a potent vasoconstrictor of
blood vessels in the brain (Kaufman et al., 1998; Volkow
et al., 1996; Wallace et al., 1996). The addictive
potential of cocaine is widely considered to be mainly
because of its block of DA reuptake (Sulzer, 2011). The
vast majority of studies have focused on elucidating the
mechanisms via which DA reuptake suppression leads
to addictive behaviors.
In this regard, the holy grail of the field has been to
understand lasting changes induced in the brain due to
this reuptake inhibition, which outlasts the presence of
the drug in the system. The main rationale for this
approach is that addictive behaviors persist well beyond
the presence of the drug in the system. One idea that
has gained considerable experimental support in the
past decade or so is that the normal learning processes
in the brain (involving the mesocorticolimbic DA system) are "hijacked" in addiction to reinforce the acquisition of the addictive drug. As is discussed in this
review, experimental results have lent considerable
support to this notion; however, recently emerging
evidence indicates this is only part of the picture (Nutt
et al., 2015). Furthermore, emerging evidence indicates
that other structures play a role in addiction as well. In
this review, the effects of cocaine on lasting changes in
the brain are discussed in a brain area-dependent
fashion, because the evidence indicates different brain
regions might play different roles in addiction (Thomas
et al., 2001; Ungless et al., 2001; Conrad et al., 2008;
Kalivas, 2009; Koob and Volkow, 2010; Luscher and
Malenka, 2011; Pascoli et al., 2012, 2014).
1. Persistent Ventral Tegmental Area Neuroplasticity
after a Single Dose. The VTA, along with the adjacent
substantia nigra (SN), forms the principle source of
DAergic projection neurons in the brain. Located in the
midbrain, it projects to the many forebrain regions
including the ventral striatum (NAc), amygdala, lateral
habenula (LHb), mPFC, ventral hippocampus (vHC),
and bed nucleus of stria terminalis (BNST) (see Fig. 1).
Although the majority of its projections are DAergic in
nature, significant populations of GABAergic and glutamatergic projection neurons have been observed as
well (Nair-Roberts et al., 2008; Stuber et al., 2010;
Hnasko and Edwards, 2012). It is believed that the VTA

887

Fig. 5. The effect of stimulant drugs on dopaminergic neurotransmission

is characterized by elevation of synaptic dopamine (DA) levels and
subsequent increases in postsynaptic neuronal responses. Cocaine blocks
the dopamine transporters (DAT), resulting in increased synaptic DA
levels due to competitive reuptake inhibition. Amphetamine and related
substances (AMPH), such as methamphetamine, are taken up into the
presynaptic neuron via the DAT, also resulting in increased synaptic DA
levels due to competitive reuptake inhibition. Because AMPHs are
lipophilic weak bases they are also capable of entering the cytoplasm via
diffusion through the membrane. Furthermore, once inside the cytoplasm
they enter secretory vesicles and cause an efflux of DA from them.
AMPHs are capable of reversing the function of DAT, causing further
increases in synaptic DA levels. In contrast, cocaine and related
stimulants do not enter the presynaptic neuron and enhance synaptic
DA levels only by inhibiting its reuptake. Either way, the end result is
enhanced signaling through DA D1- and D2-like receptors, leading to
activation or inhibition, respectively, of adenylate cyclase (AC) and
further downstream cellular responses.

plays a role in assigning "salience" to rewarding or

punishing events, and the more salient (or surprising)
an event is, the greater the chance that it is learned.
DAergic neurons in the VTA drastically increase firing
in response to unexpected rewards or punishments and
the cues associated with them (Mirenowicz and Schultz,
1996; Ungless et al., 2004; Brischoux et al., 2009).
Therefore, a drug that evokes a persistent increase in
DA neuronal firing or leads to a long-lasting potentiation of excitatory inputs to DA neuronspossibly by
inducing LTPcould in theory drive motivational
behaviors such as are observed toward salient events
(Wolf, 2002).
Initial evidence indicated that a single, noncontingent (experimenter administered) dose of cocaine led to

888

Korpi et al.
TABLE 1
Inhibition of transporter ligand binding and reuptake by cocaine and other stimulants

(A) The concentration ranges of the amphetamines AMPH, METH, and MDMA; the cathinones methcathinone, 4-MMC, and MDMC as well as cocaine and MPH needed to
displace typical DAT, SERT, NET, and VMAT2 ligands (Ki in mM). (B) The concentration ranges required to inhibit monoamine reuptake via the same transporters (IC50 in
mM). Note that methodological differences exist between the studies reported in the table.
Drug

DAT

SERT

NET

A. Inhibition of ligand binding to monoamine transporters, Ki range (mM)

Cocaine
0.20.7
0.40.7
0.40.5
Methylphenidate (MPH)
0.10.3
.1.10
0.10.3
AMPH
0.55.7
2438
0.11.0

VMAT2

References

0.1
39

(Fone and Nutt, 2005; Han and Gu, 2006)

(Bymaster et al., 2002; Fone and Nutt, 2005)
(Teng et al., 1998; Han and Gu, 2006; John and Jones,
2007; Simmler et al., 2013)
(Han and Gu, 2006; Nickell et al., 2010; Eshleman et al.,
2013; Simmler et al., 2013)
(Han and Gu, 2006; Montgomery et al., 2007b;
Eshleman et al., 2013; Iversen et al., 2013)
(Eshleman et al., 2013; Iversen et al., 2013; Simmler
et al., 2013)
(Angoa-Perez et al., 2013a; Eshleman et al., 2013;
Simmler et al., 2013)
(Eshleman et al., 2013; Simmler et al., 2013)

METH

0.54.0

9.3240

0.14.3

80-920

MDMA

1.78.3

0.62.5

0.61.8

661

Methcathinone

0.63.3

1.8.100

1.54.5

.1000

4-MMC

1.54.8

18.30

12.35

.1000

16.25

.1000

0.133.3

MDMC
2.75.0
.3095
B. Inhibition of monoamine reuptake, IC50 range (mM)
Cocaine
0.090.46
0.481.05
Methylphenidate (MPH)

0.150.26

16

0.47

AMPH
METH

0.091.6
0.010.47

.13.4
1.312

0.060.07
0.010.65

12
4.711

MDMA

0.050.48

0.0535

0.056.6

5.813

Methcathinone

0.140.36

0.0235

0.030.51

112

4-MMC

0.050.97

0.120.51

0.050.49

3.4116

MDMC

0.131.2

0.235.75

0.030.51

112

a potentiation of excitatory synaptic transmission onto

DA neurons in the VTA, and the changes observed in
response to repeated cocaine administration were similar (Ungless et al., 2001; Saal et al., 2003; Borgland
et al., 2004). This potentiation was observed by measuring the ratio of AMPAR to NMDAR-mediated currents (AMPAR/NMDAR ratio) in a neuron clamped at
a fixed voltage ex vivo, 24 hour after cocaine had been
administered in vivo. One advantage of this protocol,
which has been widely used since in the field for cocaine
and other drugs of abuse, is that lasting changes induced
in vivo can be observed (as the drug has cleared the
system). This potentiation of excitatory synaptic transmission returns to normal levels when assessed a week
later (Ungless et al., 2001). This astounding finding
indicates that a single dose of cocaine might be sufficient
to induce lasting synaptic changes in the VTA and
possibly alter activity in downstream targets. In this
regard, a recent report further characterized the earlier
findings and demonstrated that only VTA DA neurons
projecting to the NAc shell and not to the mPFC are
potentiated on exposure to cocaine (Lammel et al., 2011).
Glutamate receptor neuroplasticity could not be elicited
in the VTA-mPFC neurons even by repeated exposure to
cocaine, whereas, in contrast to cocaine, an aversive
stimulus (a formalin injection) potentiated the synapses
of the mPFC projection in the VTA. Furthermore,
optogenetic activation of inputs from the laterodorsal

(Bennett et al., 1995; Carroll et al., 1995; Meltzer et al.,

2006)
(Gatley et al., 1996)
(Markowitz et al., 2006)
(Fone and Nutt, 2005; Baumann et al., 2013;)
(Cozzi et al., 1999; Baumann et al., 2012; Eshleman
et al., 2013)
(Cozzi et al., 1999; Baumann et al., 2012; Eshleman
et al., 2013)
(Cozzi et al., 1999; Fleckenstein et al., 1999; Baumann
et al., 2012; Eshleman et al., 2013)
(Lopez-Arnau et al., 2012; Baumann et al., 2012, 2013;
Eshleman et al., 2013)
(Cozzi et al., 1999; Fone and Nutt, 2005; Baumann
et al., 2012; Lopez-Arnau et al., 2012; Eshleman
et al., 2013)

tegmental nucleus (LDTg, which preferentially synapse

onto VTA DA neurons projecting to the NAc lateral shell)
elicits reward, whereas activation of inputs from the LHb
(preferentially synapsing on DAergic projections to the
mPFC and GABAergic neurons in the VTA) results in
aversion (Lammel et al., 2012). These results suggest that
only the VTA DA neurons involved in reward processing
are affected (further discussed within this section concerning cocaine effects in the NAc and mPFC).
The increase in AMPAR/NMDAR ratio is due to
increased AMPAR currents, which is mainly due to
insertion of Ca2+-permeable GluA2 subunit-lacking
AMPAR receptors (Fig. 6) (Mameli et al., 2011). However, NMDAR-dependent currents are reduced as well
(reviewed in Luscher, 2013). This reduction is due to
insertion of quasi-Ca2+-impermeable NMDARs containing GluN3A and GluN2B subunits. It has been hypothesized that GluN3A-containing NMDARs might play
a role in cocaine-evoked AMPAR plasticity as well
(Yuan et al., 2013). Therefore, removing the GluN3Acontaining NMDARs might reduce cocaine-evoked
AMPAR plasticity and mitigate its effects on downstream targets. Activation of mGlu1 receptors in the
VTA removed these NMDARs (Yuan et al., 2013).
Furthermore, functionally overriding mGlu1 receptors
in vivo made cocaine-evoked synaptic potentiation in the
VTA persistent (that is, it did not return to normal after
7 days) (Mameli et al., 2009). This suggests mGlu1

Drug-Induced Neuroplasticity

Fig. 6. Neuronal plasticity such as long-term potentiation (LTP) or longterm depression (LTD) after exposure to acute and subchronic stimulant
drugs may occur via several distinct mechanisms. Acute cocaine exposure
induces postsynaptic LTP that may occur when novel Ca2+-permeable nonGluA2 subunit-containing AMPA receptors (AMPAR) are inserted into the
postsynaptic membrane. This process is mediated by Ca2+/calmodulindependent protein kinase II (CaMKII) after its activation by Ca2+ and is also
influenced by signaling from G protein-coupled orexin and corticotropinreleasing factor (CRF) receptors and by recruitment of GluN2B and GluN3A
subunit-containing NMDA receptors (NMDAR). Synaptic LTD occurs due to
internalization of membrane-expressed AMPARs in response to elevated
Ca2+ levels or activation of metabotropic glutamate receptors (mGlu).
Another type of LTD is due to on-demand synthesis of endocannabinoids
(eCB) such as 2-arachidonoylglycerol and anandamide (shown in green) that
activate presynaptic cannabinoid CB1 receptors, resulting in inhibition of
presynaptic neurotransmitter release (not shown here; please, see Fig. 12).
Subchronic cocaine treatment may generate silent synapses mediated by
selective recruitment of GluN2B subunit-containing NMDARs into new
synaptic locations. These sites might then maturate into functional synapses
after synaptic targeting of new AMPARs.

signaling plays an important role in regulating plasticity

in the VTA, and manipulating its activity could potentially provide a means of reducing downstream changes
induced by VTA activation in the initial vulnerable
stages of usage of drugs. In addition to redistribution of
receptors, another attractive model for plasticity in the
CNS is dendritic reorganization and dendritic spine
remodeling (which influences dendritic input to the
neuron). In this regard, spine density in a subset of
VTA DA neurons (possibly the VTA-NAc DA neurons,
but this was not investigated) has been shown to increase
in response to a single noncontingent dose of cocaine and,
strikingly, only these cells exhibited an increase in
AMPAR/NMDAR ratio as well (Sarti et al., 2007).
One possible mechanism that is suggested to maintain
LTP in various neurons by enhancing AMPAR synaptic
targeting is via prolonged induction of PKMz activation
(Sacktor, 2011). Interestingly, intracellular levels of
PKMz, a member of the atypical PKC subfamily, are
increased in the VTA neurons by cocaine treatment.
Suppressing this increase in PKMz levels reversed
cocaine-enhanced excitatory synaptic transmission, the

889

enhanced AMPAR/NMDAR ratio in the VTA, and the

cocaine-induced locomotor sensitization (Ho et al., 2012;
Velez-Hernandez et al., 2013). The role of PKMz, however, is still uncertain. The above findings have been
based only on the inhibition of PKMz activity by a zetainhibitory peptide. This inhibitor may not be specific for
PKMz, and genetic inactivation models of PKMz activity
have failed to alter memory processes that were suggested to be dependent on PKMz (Lee et al., 2013a; Volk
et al., 2013). Other atypical PKC members might compensate the genetic inactivation of PKMz, suggesting
redundance of regulating mechanisms (Jalil et al., 2015).
Optogenetic activation of GABA neurons in the VTA
results in aversion and disrupts reward consumption
(Tan et al., 2012a; van Zessen et al., 2012). This
indicates that in addition to DA neurons in the VTA,
GABA neurons play a pivotal role in reward processing
as well. Bocklisch et al. (2013) found that inhibitory
dopamine-1 receptor (D1R)-expressing medium spiny
neurons (MSNs) from the NAc that strongly project to
GABAergic interneurons in the VTA exhibited cocaineevoked synaptic potentiation. This activation of MSNs
led to a disinhibition of VTA DA neurons. Therefore,
cocaine evokes increased DAergic output from the VTA,
via indirect, disinhibitory mechanisms as well.
It is evident that the drug-induced changes in the
brain are not simply dependent on the drug alone, but
the interaction of the drug with the environment the
animal is in (for discussion, see Badiani, 2013; Luscher
and Malenka, 2011). In this regard, the effects of two
neuropeptides, corticotropin-releasing factor (CRF) and
orexin (OX), which play a role in stress, arousal, and
hunger, on potentiation of cocaine-evoked synaptic plasticity, have been widely studied. Chronic noncontingent
cocaine exposure leads to a potentiation of CRFdependent AMPAR and NMDAR neurotransmission in
the VTA (Hahn et al., 2009), whereas an OX1 receptor
antagonist blocks the potentiation of excitatory neurotransmission onto DAergic neurons observed in the VTA
of cocaine-treated animals (Borgland et al., 2006). Intriguingly, OX1 antagonist simultaneously blocked locomotor sensitization as well. Activation of OX2 receptors,
on the other hand, increased release of glutamate on to
VTA DA neurons and potentiated NMDAR currents
(Borgland et al., 2008). Nonetheless, these neuropeptides
actively modulate cocaine-induced changes in VTA DA
neurotransmission (the role of CRF and OX in VTAmediated reinstatement of drug seeking is further
discussed below), emphasizing the importance of the
interaction of the environment with the drug of abuse.
The majority of the studies have focused on the role of
the VTA in initial drug taking, which might predispose
the individual to later compulsive drug seeking. However, there is a preponderance of evidence that indicates
the VTA plays a role in drug relapse as well. A variety of
factors contribute to reinstatement of cocaine seeking
after drug-seeking behaviors have been extinguished.

890

Korpi et al.

These include stress, cues related to the drug, the

context the drug was administered in, and a "priming"
injection of the drug. In this regard, footshock a
stressorreinstates cocaine seeking by releasing CRF,
which in turn leads to an activation of VTA DA neurons
via the release of glutamate (Wang et al., 2005). CRF
neurotransmission, via CRF1 and CRF2 receptors, in
the VTA promotes reinstatement, in long-access and
short-access SA protocols, respectively (Wang et al.,
2007; Blacktop et al., 2011; reviewed in Koob and
Zorrilla, 2010; Wise and Morales, 2010). Interestingly,
activation of OX1 receptors increases reinstatement of
cocaine seeking as well, in an independent manner from
the effects of CRF (Borgland et al., 2010; Baimel and
Borgland, 2012). Therefore, neuropeptides not only
modulate initial cocaine intake but play a major role
in relapse as well.
The studies discussed thus far involve administration
of cocaine by the experimenter to the animal in a noncontingent manner (nondependent on the behavior of
the animal). Studies have remarkably shown that the
effects of noncontingent and contingent administrations
on the brain are different. In the VTA, SA of cocaine
leads to a persistent synaptic potentiation, which lasts
for up to 3 months of abstinence (Chen et al., 2008).
Therefore, further studies are required to elucidate the
mechanisms underlying these disparate changes in the
VTA.
2. Changes in the Nucleus Accumbens Mediate
Cocaine Addiction and Relapse. The NAc, principally
owing to its connectivity, is believed to play a role in
initiation of movements based on emotional salience of
encountered events. The major excitatory inputs to the
NAc are from the mPFC, BLA, vHC, and thalamus.
Furthermore, the NAc receives dense projections from
the VTA, mostly DA-releasing neurons. Anatomic studies reveal a repetitive "loop-like" mesostriatal circuitry
(Haber et al., 2000). Medial aspects of the VTA project to
the shell of the NAc, projecting back to more lateral
aspects of the VTA that in turn sends projections to the
NAc core. The core then projects to the SN that projects
more dorsally to the striatum and so on. Indeed, this
loop-like circuitry has been hypothesized to be critically
involved in addictive behaviors, by virtue of its role in
reinforcement learning and eventual habit formation
(for discussion, see Everitt and Robbins, 2005). The
majority of ventral and dorsal striatal neurons are
projecting MSNs, whose activity is mostly regulated
by excitatory inputs from cortical and limbic areas
(Sesack and Grace, 2010).
Unlike in the VTA, multiple noncontingent doses of
cocaine administration are required to elicit synaptic
plasticity in excitatory synapses in the NAc (Thomas
et al., 2001), consistent with the hypothesis that the
NAc is affected due to the action of cocaine on the VTA
and its projections. Interestingly, cocaine is intracranially self-administered only into the NAc or mPFC, not

into the VTA (Wise, 1996). The direction of the synaptic

plasticity induced due to repeated cocaine administration was a huge controversy in the field that was
recently resolved. Earlier work (Thomas et al., 2001;
Beurrier and Malenka, 2002), showed a reduction in the
AMPAR/NMDAR current ratios 1014 days after repeated cocaine exposure on administration of a challenge dose of cocaine. In line with these findings,
because mPFC-NAc synapses (a major excitatory input)
on MSNs exhibited a reduced AMPAR/NMDAR ratio
(indicative of an LTD state), further LTD could not be
elicited via electrical means and the amplitude of miniEPSCs was reduced. Activation of D1Rs by DA led to an
enhanced reduction in the AMPAR-mediated synaptic
transmission, but not NMDAR-mediated synaptic
transmission in the NAc shell (Beurrier and Malenka,
2002). On the other hand, if a challenge dose of cocaine
was not administered, a potentiation of NAc excitatory
synapses is observed (Kourrich et al., 2007). Therefore,
these results together indicate that NAc excitatory
synaptic transmission is potentiated gradually on withdrawal from repeated cocaine exposure and becomes
depressed on administration of a cocaine challenge dose
(the transient depression returns to normal levels in 7
days). The mechanisms underlying the withdrawalinduced increase in AMPAR/NMDAR ratio are still
under active investigation. Using coimmunoprecipitation studies and dissociated NAc-mPFC cultures, it was
earlier shown that an increased number of AMPARs are
recruited to the cell membrane (reviewed in Wolf and
Ferrario, 2010), with no detectable change in the subunit composition of the AMPARs. However, longer
withdrawal periods were recently shown to lead to
expression of GluA2 subunit-lacking AMPARs (which
are Ca2+ permeable). Furthermore, the expression of
these receptors was correlated with incubation of cocaine craving (defined as the progressive increase of
cue-induced cocaine seeking with time of withdrawal
and abstinence). Pharmacological inactivation of GluA2
subunit-lacking AMPARs blocked the incubation of
cocaine craving as well (Conrad et al., 2008). This
indicates that Ca2+-permeable AMPARs in the NAc
are involved in increased vulnerability of relapse with
longer withdrawal times. Moreover, the increased expression of GluA2-lacking AMPARs is preceded by
a reduction in mGlu1 receptor expression. Indeed,
systemic mGlu1 activation reverses cue-induced cocaine
craving by resetting AMPAR-mediated neurotransmission to control levels (McCutcheon et al., 2011a; Loweth
et al., 2014).
Of note here are the parallelisms between the VTA
and NAc, including the increased expression of GluA2lacking AMPARs in response to a single cocaine dose
and extended withdrawal from SA, respectively, and
their reversal by mGlu1 activation (Fig. 6). These
results taken together suggest that mGlu receptor
modulators have therapeutic potential for curbing

Drug-Induced Neuroplasticity

addiction. However, it is important to note that the

expression of GluA2-lacking AMPARs in the NAc is
only observed after long-access cocaine SA protocols
and not after short-access or noncontingent protocols
(McCutcheon et al., 2011b; Purgianto et al., 2013). In
theory, an increase in AMPAR/NMDAR ratio could be
also mediated by a decrease in the number or function of
NMDAR receptors as well. In this regard, Ferrario et al.
(2012) found that the percentage of spines mediating
NMDAR currents is reduced, but not other characteristics of NMDAR function, during the abstinence from
cocaine as well.
The importance of dissecting the specific roles of
inputs to the NAc is increasingly being realized. However, intriguingly, Stuber et al. (2011) and Britt et al.
(2012) demonstrated that three major inputs to the NAc
from the vHC, mPFC, and BLA induce self-stimulation
behavior when animals are set for specific optogenetic
stimulation of these pathways. These results suggest
that intensity of excitatory input and not the origin are
important for motivated behavior, which, remarkably,
could be induced by direct optogenetic stimulation of the
NAc MSNs (Britt et al., 2012).
Another previously overlooked change is the emergence of silent synapses. Silent synapses do not express
AMPARs, and owing to the presence of NMDARs only
which are deactivated at resting membrane and slightly
depolarized potentialsare silent under normal conditions. Initially, it was believed that these synapses
were only a characteristic of the developing brain.
However, Huang et al. (2009) showed that a salient
experience such as a subchronic, noncontingent, exposure to cocaine generates de novo silent synapses in the
NAc after a short withdrawal (1 or 2 days after 5-day
cocaine treatment) when examined ex vivo (Fig. 6).
Furthermore, increasing the number of days cocaine
was administered also increased the number of silent
synapses generated, which returned to normal levels
after a prolonged withdrawal. The generation of silent
synapses recruits a CREB-dependent insertion of novel
GluN2B subunit-containing NMDARs into the postsynapses, prevention of which impairs the development of
cocaine-elicited locomotor sensitization (Brown et al.,
2011). It is tempting to speculate here that some of the
cocaine-generated silent synapses can undergo a maturation process to form fully functional synapses. Furthermore, the initial decrease in the AMPAR/NMDAR
ratio observed in the NAc on repeated cocaine administration or a challenge dose of cocaine might be due
to increased silent synapses (reviewed in Wolf and
Ferrario, 2010).
It is extremely interesting that this phenomenon of
generation of silent synapses is observed in the adult
brain; however, what is the role of silent synapses in
addiction? Two recent studies attempted to determine
the role of silent synapses in the NAc in incubation of
cocaine craving (Lee et al., 2013b; Ma et al., 2014).

891

Consistent with the earlier findings, they observed an

increase in silent synapses in the BLA-NAc shell
projections during early withdrawal from cocaine SA
regimens (Lee et al., 2013b) by comparing synaptic
failure rates in NAc MSNs in response to selective
optogenetic minimal stimulation. Furthermore, they
discovered a similar time course for reduction in silent
synapses and emergence of GluA2-lacking AMPARs
(critical for cue-induced cocaine craving as discussed
before). Inhibiting GluA2-lacking AMPARs increased
the number of silent synapses after extended withdrawal, suggesting that the silent synapses generated
in early withdrawal will express GluA2-lacking
AMPARs later. Interestingly, an optical LTD protocol
on BLA-NAc axons internalized the GluA2-lacking
AMPARs and reduced the increase in cocaine seeking
during withdrawal.
Ma et al. (2014) studied the role of silent synapses in
the other major excitatory projections to the NAc from
the mPFC. Silent synapses are generated in both
prelimbic subregion of the mPFC (PrL)-NAc core and
infralimbic subregion of the mPFC (IL)-NAc shell
projections during early withdrawal. Extended withdrawal led to a recruitment of GluA2-lacking AMPARs
in IL-NAc synapses (showing more rectification) but to
a recruitment of GluA2-containing AMPARs in PrLNAc synapses in NAc slices (showing less rectification).
Behaviorally, internalization of these receptors in ILNAc and PrL-NAc synapses, by selective optogenetic
LTD stimulation protocols, led rats to show an increase
and decrease in enhanced cocaine craving during
abstinence, respectively (further discussed in the PFC
section). Of note here are the parallels between the
similar effect of PrL and BLA manipulations on initial
cocaine seeking discussed earlier (Britt et al., 2012;
Stuber et al., 2011) and on incubation of cocaine craving
(Lee et al., 2013b; Ma et al., 2014); that is, motivated
behaviors require an excitatory drive to the NAc, which
can be from either the BLA or the PrL. Similarly,
cocaine withdrawal leads to an increase in BLA-NAc
and PrL-NAc silent synapses, reversal of which reduces
the enhancement of cocaine seeking during withdrawal/
abstinence.
These results taken together indicate that silent
synapses generated in the NAc due to chronic cocaine
exposure might eventually express AMPARs, which
owing to their higher conductivity, make the NAc
neurons more excitable, leading to increased cocaine
craving with time.
The role of silent synapses in the NAc might not be
limited to enhancement of cocaine craving during
withdrawal. A series of studies conducted by Hope and
colleagues (Koya et al., 2009, 2012) showed that induction of context-specific psychomotor sensitization
on noncontingent repeated administration of cocaine
is dependent on a very small subset of neurons (an
ensemble consisting of 23% of neurons in the NAc), which

892

Korpi et al.

can be visualized in c-fos-lacZ transgenic rats. Selective inactivation of these neurons by b-galactosidaseinduced formation of a cell toxin daunorubicin impaired
psychomotor sensitization. These highly active neurons
produced higher levels of silent synapses on cocaine
sensitization than the general neuron population,
which unlike the whole NAc persisted up to 611 days
after sensitization. However, the precise role of these
silent synapses is yet to be determined.
Although many earlier reports have studied the role
of NAc in cocaine addiction without considering the
heterogeneity in the NAc, it is increasingly being
realized that the NAc has distinct subcircuits. The main
population of neurons in the NAc is the MSNs. These
constitute 95% of NAc neurons and are the major class
of projection neurons from the NAc. MSNs have been
further subdivided depending on whether they express
D1Rs or dopamine-2 receptors (D2Rs). Akin to the muchstudied dorsal striatum, these two classes of MSNs form
distinct projection pathways. D1R-expressing MSNs
constitute the "direct pathway" that projects directly
to the midbrain, whereas D2R-expressing MSNs form
the "indirect pathway" that projects to the midbrain via
the ventral pallidum. Moreover, these classes of MSNs
have different electrophysiological and neurochemical
characteristics (Cepeda et al., 2008; Planert et al.,
2013). Hence, a host of recent studies have discovered
differing roles subserved by these MSNs in addictive
behaviors. Nonspecific optogenetic inhibition of NAc
core neurons reduces cocaine-primed cocaine reinstatement (Stefanik et al., 2013b); however, this effect is only
replicated by inhibiting the pallidal projections from the
NAc (indirect pathway) and not the nigral projections
(direct pathway) (Stefanik et al., 2013a). However,
another study found that optogenetic activation of
channel rhodopsin-2 expressing D2R-MSNs in the NAc
suppressed responding for cocaine, whereas their inhibition using a chemogenetic approach (designer
receptor exclusively activated by a designer drugmediated protocol) enhanced the motivation (higher
breakpoints of responding) to work for cocaine (Bock
et al., 2013).
The differences observed in these results might be
due to the different stimulation protocols employed and
to different behavioral tests. Stefanik et al. (2013a)
stimulated NAc-pallidal axons, whereas Bock et al.
(2013) manipulated D2R-MSNs directly. Alternatively,
D2R-MSNs might only be involved in compulsive cocaine SA [as measured by increased breakpoints for
responding to cocaine in Bock et al. (2013)] and not
cocaine-primed reinstatement behavior, which was
used in Stefanik et al. (2013a). In this regard, one study
(Lobo et al., 2010) selectively deleted the BDNF receptor TrkB in either D1R- or D2R-MSNs. BDNF has
been widely implicated in mechanisms underlying
synaptic plasticity. By using the CPP paradigm, genetic
deletion of TrkB expression in D1R- or D2R-MSNs

increased and decreased the rewarding properties of

cocaine, respectively. These effects were mimicked by
optogenetic activation of D1R- or D2R-MSNs, respectively. Another ingenious study (Pascoli et al., 2014)
found that incubation of cue-associated cocaine craving
is correlated with rectifying AMPAR currents and a reduced AMPAR/NMDAR ratio of mPFC-NAc shell synapses on to D1R-MSNs. On the other hand, AMPAR/
NMDAR ratio increased at vHC-NAc D1R-MSNs. Optogenetic reversal of these changes in both inputs, using
optogenetic LTD protocols, abolished cue-induced cocaine seeking. Intriguingly, LTD induction at the
mPFC-NAc synapses impaired response discrimination
in the cocaine-seeking task, whereas a reduction in
responses was observed when LTD was induced at
vHC-NAc synapses. These studies taken together indicate that D1R-MSNs are involved in promoting initial
cocaine-seeking behaviors and reinstatement of cocaineseeking behaviors as well. More specifically, inputs from
the mPFC to the NAc shell D1R-expressing neurons
might promote responding to the correct lever, whereas
vHC inputs might promote responding per se. D2R-MSNs
initially inhibit cocaine seeking, but might promote
compulsive cocaine seeking. Nonetheless, further studies
are required to clarify the precise roles of these subpopulations of NAc MSNs in addictive behaviors.
In concert with the changes in AMPAR expression in
the NAc, withdrawal from chronic noncontingent cocaine exposure results in structural changes in MSN
dendrites. A short withdrawal period (2 days) results in
increased dendritic spine formationmediated by a
variety of transcription factors and epigenetic mechanisms as discussed laterin both D1R- and D2R-MSNs,
whereas this increase is only sustained in D1R-MSNs
after prolonged withdrawal of 30 days (Lee et al., 2006).
In addition, both D1R- and D2R-MSNs exhibit dendritic
remodeling on chronic cocaine exposure, which can be
mediated by D1R activation (Li et al., 2012; Zhang et al.,
2012). Furthermore, spine structure varies considerably as well. Withdrawal from repeated noncontingent
cocaine exposure results in increased spine diameter.
Subsequent cocaine priming elicits a biphasic change in
spine diameter: transiently further increasing the size
of the spine (45 minute after injection) and then reducing it when observed 24 hours later. This change in
spine diameter is paralleled by changes in AMPAR
expression, which has been shown to transiently increase (30 minutes after administration) on cocaine reexposure before decreasing (24 hours later); and then
subsequently increasing again as the duration of withdrawal is prolonged (Boudreau et al., 2007; Kourrich
et al., 2007; Anderson et al., 2008).
Reorganization of the cytoskeletal architecture of the
neuron, or lack thereof, is critical for synaptic plasticity
and stability. Likewise, the structural changes in
dendrites of MSNs are associated with changes in the
cytoskeletal architecture as well. Withdrawal from

Drug-Induced Neuroplasticity

repeated cocaine administration produces lasting elevation in polymerized filamentous actin in the NAc, due
to suppression of actin cycling by reducing the active
form of Rac1, a Rho GTPase that controls actin remodeling (Dietz et al., 2012). Reducing actin polymerization
or increasing depolymerization results in reduced dendritic spine density and explains the transient increase
in spine head diameter on cocaine priming and behavioral sensitization (Toda et al., 2010; Dietz et al., 2012).
Indeed, knockout of Rac1 is sufficient to increase the
density of immature dendritic spines in the NAc. Hence,
these studies establish a mechanistic link between the
behavioral responses, changes in spine morphology, and
actin cycling.
In agreement with these findings, PSD-localized
kalirin-7 (Kal-7; a brain-specific guanine nucleotide
exchange factor) and its downstream effectors Rac1
and p21-activated kinase PAK are increased in the NAc,
alongside with AMPAR surface expression and spine
density on withdrawal from a repeated cocaine administration regimen (Wang et al., 2013d). Single-hairpin
RNA (shRNA)-mediated silencing of Kal-7 in the NAc
before cocaine exposure eliminates all these changes
(increased AMPAR expression and spine density). This
Kal-7 silencing, however, failed to prevent locomotor
sensitization indicating the involvement of other mechanisms in eliciting this behavior. Incentive sensitization, the ability to rapidly learn to self-administer
cocaine, was also impaired. Interestingly, constitutive
Kal-7 knockout enhanced cocaine SA (Kiraly et al.,
2013), which might be due to compensations by other
kalirin isoforms.
In addition to intracellular biochemical pathways
associated with the cytoskeletal architecture, extracellular CAMs are affected by cocaine as well. In this
regard, integrins are CAMs in the ECM that are
involved in the regulation of synaptic plasticity, including glutamate receptor trafficking. Mirroring the
other changes in the NAc, b3 integrin subunit is reduced
in the NAc core 24 hours after a SA cocaine protocol.
However, after 3 weeks of abstinence and extinction, the
levels are elevated (Wiggins et al., 2011). Moreover,
cocaine priming further regulates the levels of b3
integrin. Daily NAc microinfusions of a peptide ligand
that mimics a protein binding to integrins before SA or
reinstatement, inhibited cocaine-induced drug seeking
and normalizes the surface expression of AMPARs.
Repeated cocaine exposure and the subsequent withdrawal results in other changes in MSNs synaptic and
extrasynaptic neurotransmission, in addition to alterations in AMPAR expression, dendritic arborization,
silent synapses, spine head length, and spine density. In
general, D1R-MSNs exhibit decreased membrane excitability on withdrawal from repeated cocaine exposure,
whereas D2R-MSNs show no change in membrane
excitability (Kim et al., 2011). Furthermore, cocaine
disrupts the normal glutamate homeostasis necessary

893

for maintenance of appropriate levels of glutamate in

the synaptic and extrasynaptic (a much larger pool)
spaces. In this regard, the extracellular glutamate in
the NAc is regulated by cysteine/glutamate exchanger
xCT and glutamate transporter GLT-1 in glia (Baker
et al., 2003; Knackstedt et al., 2010). Withdrawal from
repeated cocaine injections or SA substantially reduces
extracellular glutamate, glutamate uptake, and the
expression of these transporters (Baker et al., 2003;
Knackstedt et al., 2010). Extrasynaptic glutamate
normally binds to presynaptic mGlu2/3 receptors and
reduces synaptic glutamate release. Therefore, chronic
cocaine exposure results in an increase in the synaptically releasable pool of glutamate (reviewed in Kalivas,
2009; Wolf and Ferrario, 2010). Importantly, N-acetylcysteine, a well-tolerated prodrug for increasing cysteine levels and used to replenish liver glutathione levels
in paracetamol (acetaminophen) intoxication, has been
shown to enhance extrasynaptic glutamate levels and to
reduce relapse to cocaine in rodents and in early studies
on cocaine addicts (Baker et al., 2003; Schmaal et al.,
2012; LaRowe et al., 2013). Hence, cocaine abuse results
in a host of changes in MSNs in the NAc; indeed, it has
been suggested that these changes in glutamate transmission and membrane excitability are linked to
AMPAR regulation (Wolf and Ferrario, 2010) to mediate the behavioral phenotype.
3. Altered Gene Expression in the Nucleus Accumbens
in Cocaine Seeking and Relapse. Not all individuals
have an equal propensity to develop addiction. In this
regard, approximately half of a persons risk for addiction is genetic (Goldstein, 2001; Wang et al., 2012a).
Therefore, long-lasting alterations in gene regulation
upon cocaine exposure, via transcriptional or epigenetic
mechanisms, are likely to play a pivotal role in addiction
(reviewed in Robison and Nestler, 2011). Transcription
factors are proteins that regulate gene expression in
response to intracellular signaling pathways by binding
to certain sites on the DNA and subsequently altering
the expression of the genes. Genetic material in the
nucleus is packed into chromatin complexes (DNA,
histones, and other proteins), generally split in to two
classes: euchromatin (loosely packed DNA around
histones) and heterochromatin (densely packed, hence
less active), depending on the activity states of the
chromatin. Epigenetic changes are considered alterations in this packing and thus alter activity of different
regions of DNA. Regulation of genetic activity via
transcriptional and epigenetic mechanisms involves
a myriad of processes; the field has focused mainly on
a few mechanisms that will be discussed here, including
notable work on transcription factors like DFosB,
CREB, NFkB, and MEF2, and epigenetic histone
acetylation and methylation. Because the majority of
these alterations in levels of transcription factors and
epigenetic regulation are observed on repeated exposure to cocaine, most of the studies have focused on the

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NAc. Hence, a considerable amount of work is still

needed in this promising, budding field to elucidate the
role of numerous other factors and structures.
Expression of the Fos family of transcription factors
in the NAc is increased transiently on acute cocaine
exposure. However, only DFosB (which is only slightly
induced on acute exposure), due to its longer half-life,
accumulates on repeated drug exposure selectively in
NAc D1R-MSNs (Hope et al., 1994; Moratalla et al.,
1996; Kelz et al., 1999; reviewed in Nestler et al., 2001).
Induction of DFosB chronically in D1R-MSNs or nonselectively in the MSNs increases the rewarding properties of cocaine and other natural rewards as assessed
by CPP, enhances the locomotor response, and promotes
SA; surprisingly, a short-term change in DFosB reduces
the rewarding properties of cocaine as assessed by CPP
(McClung and Nestler, 2003; Grueter et al., 2013).
Intriguingly, overexpression of DFosB in D1R-MSNs
decreased the AMPAR/NMDAR ratio and increased
silent synapses on these neurons in the NAc shell and
core, whereas overexpression in D2R-MSNs resulted in
increased excitatory synaptic strength as assessed by
the AMPAR/NMDAR ratio and in decreased silent
synapses in the NAc shell only. Furthermore, density
of immature spines in D1R- but not D2R-MSNs increased as well on respective overexpression of DFosB in
these neuronal populations (Grueter et al., 2013).
Taken together, these findings indicate that DFosB
plays a critical role in mediating the rewarding and
locomotion-inducing properties of cocaine.
Alterations in induction of DFosB in the NAc might
play a role in relapse as well. Damez-Werno et al. (2012)
demonstrated that after prolonged withdrawal from
repeated cocaine administration, DFosB induction and
accumulation in the NAc was enhanced by cocaine reexposure. This increased induction might be due to
sustained elevation of DFosB, and increased dendritic
spine density as well, in D1R-MSNs after prolonged
withdrawal. D2R-MSNs, however, only exhibited increased DFosB and dendritic spine density after short
withdrawal periods (2 days) on cessation of a repeated
cocaine administration regimen (Lee et al., 2006).
CREB, another transcription factor, seems to increase in both major subtypes of NAc MSNs. CREB,
unlike DFosB, reduces the sensitivity to the rewarding
effects of cocaine (tolerance) and increases SA and
relapse via negative reinforcement. For instance, the
k-opioid peptide dynorphin, regulated by CREB, suppresses DA transmission to the NAc via the activation of
k-opioid receptors, thus impairing rewarding behaviors
(Carlezon et al., 1998; Larson et al., 2011; Muschamp
et al., 2011; Ehrich et al., 2014). Furthermore, the
induction of DFosB in the NAc is dependent on CREB
and serum response factor (Vialou et al., 2012). Deletion
of CREB and serum response factor, but not either one
alone, eliminates induction of DFosB on cocaine exposure in the NAc, reduces the rewarding properties of

moderate doses of cocaine as assessed by CPP, and blocks

locomotor sensitization at higher doses of cocaine. Interestingly, deletion of CREB alone has the opposite
effect, that is, an increase in behavioral sensitization and
CPP in response to cocaine (Carlezon et al., 1998; Walters
and Blendy, 2001; McClung and Nestler, 2003). The
sustained expression of DFosB in the NAc and the
accompanied increase in dendritic spines and behavioral
responses, requires CaMKIIa, which is increased on
chronic cocaine exposure as well (Robison et al., 2013).
Importantly, DFosB and CaMKIIa are increased in the
postmortem NAc of human cocaine addicts compared
with matched normal controls without histories of major
psychiatric illnesses (Robison et al., 2013).
Other transcription factors have been implicated in
cocaine addiction as well. For instance, reduction of
myocyte enhancer factor 2 activity in the NAc is required for cocaine-induced increased spine density and
possibly is linked to behavioral sensitization as well
(Pulipparacharuvil et al., 2008). Similarly, nuclear
factor kappa-B (NFkB), involved in maintaining cell
structure, is induced by chronic cocaine exposure.
Elevation and reduction of NFkB signaling in the NAc
increased and decreased (and also prevented cocaineinduced increase in) the number of dendritic spines on
NAc neurons, respectively. Furthermore, inhibition of
NFkB makes cocaine less rewarding (Russo et al., 2009).
The N-terminus of the histone (the histone tail) is
particularly susceptible to modifications. Relevant histone tail modifications involve the enzymes histone
acetyltransferases, whereas histone deacetylases (HDACs)
catalyze the removal of acetyl groups. Similarly, histone
methyltransferases and histone demethylases catalyze
the addition and removal of methyl groups, respectively. Generally, acetylation is associated with increased activity and methylation with reduced gene
activity.
Earlier studies found conflicting results on cocaineinduced behavioral responses with inhibition of HDAC.
Two studies found that systemic treatment with HDAC
inhibitors, trichostatin A and phenylbutyrate, reduced
the motivation for SA of cocaine and cocaine-plus-cued
reinstatement of drug seeking (Romieu et al., 2008,
2011), whereas a third one (Kumar et al., 2005) reported
increased rewarding effects of cocaine as assessed by
CPP and stimulation of cocaine-induced locomotion.
Furthermore, chronic cocaine exposure increased
DFosB, cdk5, and BDNF in the NAc (as discussed
earlier). This increase is mirrored by an increase in
H3 acetylation at promoters of cdk5 (regulated by
DFosB) and BDNF (Kumar et al., 2005). Although these
studies indicated a link between histone modifications
and transcription factors in cocaine addiction, their role
was not clear because of the conflicting results.
However, the use of specific experimental manipulations in more recent studies has resolved this controversy. Kennedy et al. (2013) found that only prolonged

Drug-Induced Neuroplasticity

knockdown of HDAC1, not HDAC2 or HDAC3, in the

NAc reduced cocaine-induced behavioral plasticity.
Overexpression of HDAC3, 4, or 5 in the NAc, on the
other hand, suppressed cocaine-induced acquisition of
CPP; that is, the cocaine-context association took longer
to form (Rogge et al., 2013). Furthermore, chronic
cocaine exposure or stress decreases HDAC5 function
in the NAc; conversely, loss of HDAC5 in the NAc
increases the responsiveness to chronic cocaine or stress
as assessed by the CPP paradigm (Renthal et al., 2007).
The role of methylation, and the associated enzymes,
in cocaine addiction has been studied as well. Repeated
cocaine exposure reduces overall levels of histone 3
lysine 9 dimethylation and lysine dimethyltransferase
G9a in the NAc as well (Maze et al., 2010). DFosB
downregulates G9a, which results in reduced histone 3
lysine 9 dimethylation. Experimental reduction of G9a
increases dendritic spine plasticity in the NAc and
rewarding properties of cocaine as assessed by CPP.
This reduction in G9a is observed in both D1R- and D2RMSNs. However, the effects of experimental manipulation of G9a in the MSN subpopulations are different.
Similar to a nonspecific downregulation of G9a in MSNs
(Maze et al., 2010), knockout of G9a in D2R-MSNs
increased cocaine reward and locomotor sensitization,
whereas knockout in D1R-MSNs had the opposite
effects (Maze et al., 2014). Intriguingly, knockout of
G9a in D2R-MSNs resulted in these neurons having
a phenotype similar to D1R-MSNs.
On another note, experimental reduction of G9a in
the NAc also results in a depression-like phenotype.
This phenotype emerges on chronic cocaine exposure as
well. Indeed, increasing G9a activity in the NAc after
chronic cocaine exposure rescues the depression-like
phenotype (Covington et al., 2011). It has been suggested that G9a reduction by chronic cocaine exposure
might result in development of stress-related illness in
addicts. Further studies are warranted to determine if
this is indeed the case.
4. Progressive Involvement of the Dorsal Striatum.
A popular hypothesis for addiction proposes that addiction initially depends on the ventral striatum (including
the NAc), but progressively engages and hijacks the
circuitry in the dorsal striatum, which is normally
required for habitual learning. It is suggested that this
shift might mirror the change from voluntary to involuntary (or habitual) drug intake in addiction (Robbins
and Everitt, 1999; Everitt and Robbins, 2005, 2013).
This hypothesis fits well with the human literature on
cocaine addiction, which implicates the dorsal striatum
in cocaine addiction. Because a substantial amount of
human imaging studies compare cocaine addicts to
nonaddicted individuals, assuming this hypothesis
were true, it is not surprising that altered activity in
the dorsal striatum is observed. Consistent with this
hypothesis (and the human literature), Ito et al. (2000,
2002) observed increased DA release in the dorsal

895

striatum, but not NAc, on presentation of cocaineassociated cues after prolonged exposure to cocaine.
Similarly, blocking (or transiently inactivating) DA
receptors of dorsal striatum, but not those of NAc,
reduced the cocaine-seeking behaviors after protracted
cocaine exposure (Vanderschuren et al., 2005; Zapata
et al., 2010). On the basis of these findings, the authors
postulated that initial dependence on the VTA-NAc
pathway might be replaced by an increasing involvement of the nigrostriatal pathway as drug seeking
becomes more habitual (that is, on prolonged exposure
to the drug). It is well known that midbrain DAergic
projections to the striatum and backprojections to the
midbrain form a "spiraling" cascade: medial VTA projects to the NAc, which backprojects to lateral VTA, and
so on (progressively involving the dorsal striatum and
SN as well, Fig. 1)(Haber et al., 2000). To test whether
this circuitry might be involved in cocaine addiction, an
elegant study disconnected various parts of this serial
circuitry using alpha-fluphentixol (an antipsychotic
with strong antagonism at D1, D2, D3, and histamine
H1 receptors) and found a selective reduction in habitual drug seeking (Belin and Everitt, 2008).
Although the ventral striatum is critical for voluntary
behavior, a host of studies also implicate the dorsal
striatum in goal-directed (action-outcome) and habitual
(stimulus-response) behaviors. More specifically, the
dorsomedial striatum is involved in goal-directed behavior, whereas the dorsolateral striatum is involved in
habitual behavior (Yin et al., 2004, 2005a,b; Corbit and
Janak, 2010; Corbit et al., 2012) (Fig. 1). In agreement
with these findings, repeated cocaine exposure has been
shown to perturb the electrophysiological properties of
neurons in the dorsomedial striatum and to reduce goaldirected behavior as well. Furthermore, administration
of N-acetylcysteine reversed the behavioral deficits and
the associated changes in properties of dorsomedial
striatal neurons (Corbit et al., 2014) (see also discussion
in section II.D on alcohol).
5. Changes in Lateral Habenula and Rostromedial
Tegmental Nucleus Contribute to Aversive Symptoms of
Cocaine Withdrawal. Although "withdrawal symptoms"
from cocaine are not as pronounced as from some other
drugs of abuse, a depression-like phenotype is observed,
which might result in increased drug intake (Barr et al.,
2002; Koob and Le Moal, 2008). Thus, given the role of
the lateral habenula (LHb) in depressive disorders, it
is not surprising that an interest in its role in drug
addiction has recently emerged (Li et al., 2011;
Maroteaux and Mameli, 2012; Zuo et al., 2013; Lecca
et al., 2014). In this regard, earlier studies demonstrated that the LHb inhibits the VTA via its projections to the GABAergic rostromedial tegmental
nucleus (rmTg), promoting avoidance behaviors (Jhou
et al., 2009b; Kaufling et al., 2009; Balcita-Pedicino
et al., 2011; Stamatakis and Stuber, 2012) (Fig. 1). By
using an ex vivo preparation similar to earlier studies in

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the VTA and NAc (discussed earlier), it was recently

shown that two prior in vivo, noncontingent doses of
cocaine selectively enhance glutamatergic transmission
onto LHb neurons projecting to the rmTg (as well as
increasing excitability of these neurons by reducing K+
currents) (Meye et al., 2013, 2015). These changes
persisted for 1 week, whereas a chronic cocaine regimen
(5 noncontingent doses) results in similar persistent
changes for 2 weeks (at which point, depressive-like
"withdrawal" behaviors were observed). Furthermore,
the changes were dependent on GluA1 subunitcontaining AMPAR trafficking in these neurons. Its
inhibition by virally expressed GluA1 C-terminal peptide resulted in a reduction in depression-like behaviors
on withdrawal and in persistent neuronal changes in
the LHb (Meye et al., 2015). Therefore, these studies
implicate the LHb-rmTg-VTA axis in the negative
symptoms associated with cocaine withdrawal. Interestingly, initially acute cocaine results in a reduction of
activity of a subpopulation of LHb neurons, followed by
increased activity, perhaps in putative rmTg-projecting
neurons (Lecca et al., 2014), suggesting that these
neurons might disinhibit VTA DA neurons during the
early pleasant experience on cocaine intake, but might
later reverse roles, leading to withdrawal symptoms.
Intriguingly, stimulation of the midbrain DAergic
structures modulates activity of pain-associated LHb
neurons as well, indicating that there are functionally
relevant connections from the VTA to LHb as well (Shen
et al., 2012). Obviously, further studies are required to
determine the roles of various LHb pathways in cocaine
addiction. In addition, to the aforementioned role of
LHb in cocaine addiction, stimulants have been shown
to induce strong excitation of LHb efferents to the rmTg
(further discussed in section II.A.11).
6. Complex Alterations in the PFC. The role of the
PFC in cocaine addiction is more complex. A single dose
of cocaine fails to elicit increased glutamate receptor
neuroplasticity in those VTA DA neurons that project
the mPFC (Lammel et al., 2011), although the same
treatment induces a prolonged increase (at least 21
days) in AMPAR/NMDAR current ratios of those VTA
DA neurons that project to NAc medial shell. The
mesocortical DA neurons might be more responsive to
aversive stimuli (Lammel et al., 2011). These findings
indicate that the PFC might not be involved in initial
cocaine-seeking behaviors.
DA neurons in the VTA responsive to aversive stimuli
project to the mPFC (Lammel et al., 2012). Interestingly, there is considerable evidence from early studies
implicating excitatory neurotransmission from the
mPFC to the NAc in cue-induced reinstatement (for
discussion, see Kalivas, 2009). However, the role of
mPFC inputs might be subtler. Optogenetic inhibition
of PrL-NAc core projections reduces cocaine-primed
reinstatement of cocaine seeking, and activation of the
PrL pathways is required for the cue-associated

transient increase of dendritic size and synaptic strength

in the NAc (Gipson et al., 2013; Stefanik et al., 2013b;
Shen et al., 2014). Furthermore, as discussed earlier,
Pascoli et al. (2014) found that optogenetic reversal of
cocaine-evoked plasticity in mPFC-NAc shell D1R-MSN
synapses attenuates response discrimination in cueinduced cocaine reinstatement. In addition, Ma et al.
(2014) present evidence that PrL-NAc inputs promote,
whereas IL-NAc inputs reduce, the enhancement of
cocaine craving during withdrawal. PrL neurons show
enhanced responsiveness to cocaine-associated cues, unlike the IL neurons (West et al., 2014). BDNF in the IL
promotes extinction of CPP (Otis et al., 2014). Taken
together, these findings indicate that PrL-NAc activation
promotes cue-induced cocaine seeking, whereas IL-NAc
activation promotes extinction of cocaine seeking.
On the other hand, pyramidal neurons in the PrL of the
mPFC in "compulsive" cocaine-seeking rats (a subset of
rodents that will seek cocaine despite negative consequences; more truly representative of addictive individuals) are less excitable after an extended SA protocol.
This compulsive cocaine seeking is increased or decreased
by optogenetic inhibition and activation of PrL pyramidal
neurons, respectively (Chen et al., 2013a). It is intriguing
to speculate that in these compulsive cocaine-seeking
rats, VTA-PrL synaptic excitability, which should convey
aversive values of encountered stimuli (Lammel et al.,
2011), is downregulated as well. This would reduce
aversion and hence enable cocaine seeking even at the
cost of "aversive consequences." However, further studies
are needed to determine if this indeed is the case. Another
possible explanation of these findings might be that these
rodents, due to reduced activity in the PrL, exhibit
reduced flexibility in switching behaviors (a function
subserved by the mPFC)or perseveranceon introduction of aversive consequences. Indeed, Allen and Leri
(2014) found that lesions of the PrL (which might have
similar functional consequences as hypoactivity of PrL
pyramidal neurons) resulted in increased perseverance
after chronic cocaine exposure.
Similar to the hypoactivity observed in the PrL, cocaine
SA also leads to a hypoactivity of pyramidal neurons in
the orbitofrontal cortex (OFC; although the underlying
mechanisms are different), a locus of decision-making and
insight in the brain (Lucantonio et al., 2014). Furthermore, this correlated with a lack of insight in the animals
(lack of expectation of a larger reward summation, when
two different cues were presented at the same time, as
shown by unchanged responding), which was normalized
by optogenetic stimulation of the OFC neurons. Moreover,
the VTA-OFC-BLA forms a functional circuit for contextinduced drug reinstatement. Specifically, contextual reinstatement of cocaine seeking in extinguished rats is
dependent on OFC-BLA activity and D1R signaling in the
OFC (Lasseter et al., 2011, 2014), as demonstrated by
local inactivation with microinfusions of GABAA/GABAB
agonist cocktail and D1R antagonist.

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7. Hippocampal Functional Changes. Although the

HC is one of the principal regions in the brain involved
in spatial and contextual memory processing, not much
attention has been paid to the role of the HC in cocaine
addiction. An earlier study (Vorel et al., 2001) observed
reinstatement of cocaine-seeking behaviors after theta
burst electrical stimulation of the ventral subiculum
(part of the vHC). This reinstatement was mediated by
HC glutamatergic projections to the VTA, as it could be
mimicked by intra-VTA infusion of NMDA and blocked
by infusion of an NMDAR antagonist. Similarly, a trisynaptic pathway originating from the CA3 of the dorsal
HC to the VTA (via the lateral septum), which excites
DA neurons, is required for reinstatement of cocaine
seeking on exposure to the context (Luo et al., 2011).
Optogenetically inducing LTD in vHC-NAc D1R-MSN
synapses reduces the number of responses on cueassociated reinstatement of cocaine seeking, in contrast
to induction of LTD on mPFC-NAc D1R-MSN synapses,
which diminishes response discrimination (Pascoli
et al., 2014). Taken together, these findings indicate
that the HC plays a role in reinstatement of cocaineseeking behaviors. However, further studies are required to discern the precise roles of specific subregions
in the HC in cocaine addiction.
Like in other neuropsychiatric disorders, dysfunctional
adult neurogenesis has been observed to play a role in
cocaine addiction as well. Reducing hippocampal neurogenesis increases cocaine SA. Furthermore, neurogenesis
is also negatively correlated to chronic cocaine intake and
seeking behaviors (Noonan et al., 2008, 2010). Cocaine SA
reduces dentate gyrus neurogenesis, which returns back
to baseline during extinction (Deschaux et al., 2014). LFS
of the dorsal or ventral HC after extinction session
prevented the increase in neurogenesis and actually
enhanced cocaine seeking after a priming dose. Further
studies are required to elucidate the precise mechanisms
underlying these effects.
Selective reactivation of the dorsal dentate gyrus
neurons originally involved in encoding a rewarding
memory in an aversive environment reverses the valence
of that rewarding memory (its ability to evoke appetitive
behaviors as assessed by CPP) (Redondo et al., 2014). A
similar reactivation of the neurons originally active in the
BLA did not reverse the valence of the memory (Redondo
et al., 2014). However, selective ablation (CREB-Cre in
iDT mice expressing cell-specific diphtheria toxin receptor after cre-recombinase induction) or silencing
(chemicogenetic silencing with CREB-hM4Di designer
receptor exclusively activated by a designer drug receptors) of "cocaine-memory-trace"-activated neurons in the
lateral nucleus of amygdala (LA; about 10% of the
neurons that increased expression of CREB in response
to cocaine administration) disrupted the expression of
a previously acquired cocaine-context-related memory,
because the animals failed to show CPP (Hsiang et al.,
2014). Interestingly, when these animals were taken

897

through extinction session and tested later for cocaineinduced reinstatement, the small number of previously
activated LA neurons was needed also for this kind of
drug memory. Taken together, these findings indicate
that in these HC and amygdala structures, a small subset
of neurons are required for reward processing and are
possibly hijacked during cocaine-seeking behaviors.
The hippocampal formation plays a role in spatial
navigation and memory consolidation. In this regard,
HC "place cells" fire in a specific location in an environment (OKeefe and Dostrovsky, 1971; Colgin et al.,
2008). When the animal traverses space, sequential
HC place cell firing is observed, encoding the animals
trajectory. These sequences are replayed during subsequent sleep and quiet wakefulness, which are proposed to consolidate this memory (Skaggs and
McNaughton, 1996; Davidson et al., 2009). However, it
was recently demonstrated that replay or reactivation
of HC activity does not simply depend on experience,
but might be modulated by the behavioral state of the
animal, including inputs from the VTA, and the environment (Gupta et al., 2010; McNamara et al., 2014).
Such off-line reactivation of neurons associated with
rewarding behaviors is observed in the NAc as well
(Lansink et al., 2008), possibly providing consolidating
memories with a motivational component. Interestingly, using multineuron recordings, reactivation of
HC place cells leads to activation of striatal reward
site-related neurons as ensembles in sleep, followed
shortly after HC sharp wave-ripple complexes, suggesting that the HC plays a pivotal role in consolidation of
reward-related memories (Lansink et al., 2009). Furthermore, contextual fear conditioning remaps HC cells
(Moita et al., 2004). These studies indicate that the HC
is critical for forming associations between the context
and appetitive or aversive behaviors. This raises the
intriguing possibility that cocaine might alter hippocampal ensemble activity, and thus spatial memory
processing of the cocaine-associated cues and context.
8. Bed Nucleus of Stria Terminalis and Amygdala
are Involved in Stress-Induced Reinstatement of Cocaine Seeking. The BNST is required for stress-, cue-,
or yohimbine-associated reinstatement of cocaine seeking (Buffalari and See, 2011), based on experimental
inactivation experiments of the BNST with locally
infused GABAA and GABAB agonists. CRF in the BNST,
possibly via projections from the CeA, induces reinstatement (Erb and Stewart, 1999; Erb et al., 2001a,b).
Furthermore, noradrenergic neurotransmission in the
BNST or CeA is required for stress-induced but not
cocaine-induced reinstatement (Leri et al., 2002). Finally, stress-induced reinstatement of cocaine seeking
requires activity in a ventral BNST-VTA pathway,
which releases CRF in the VTA. This release of CRF is
modulated by b2 adrenergic receptors in the BNST
(Vranjkovic et al., 2014). Therefore, the CeA-BNSTVTA system forms a functional circuit involved in

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stress-induced reinstatement of cocaine seeking. The

connections are complicated, as illustrated by reciprocal
connections between the BNST and VTA, with both
GABA and glutamate neurons from the BNST targeting
VTA GABA neurons. When selectively activated by
optogenetics, BNST-VTA GABA projection disinhibits
the VTA DA neurons, whereas BNST-VTA glutamate
projection indirectly inhibits the VTA DA neurons,
producing rewarding and aversive/anxiety-like responding, respectively (Jennings et al., 2013).
9. Effects of Adolescent Cocaine Exposure.
Adolescents are more prone to develop cocaine addiction
than adults; they administer cocaine more readily, are
more sensitive to lower doses, show increased activation
of VTA DA neurons, and show greater escalation of
cocaine intake (reviewed in Gulley and Juraska, 2013).
Indeed, a significant proportion of studies (specifically,
the majority of ex vivo electrophysiology studies) discussed in this review were performed in adolescent
animals, because the experiments are less tedious and
the results more pronounced. However, the effect of
adolescent exposure to cocaine on adult behavior has
not been widely studied.
Of note are two studies, which employed a novel
escalating "binging" cocaine administration protocol in
adolescent rats (12 days between P35 to P46) and its
effects on subsequent behavior during adulthood. This
binging protocol was aimed at recapitulating human
adolescent drug use. Black et al. (2006) demonstrated
that these rats displayed increased responsiveness to the
stimulant effects of cocaine in adulthood. Furthermore,
they exhibited "abnormally" rapid shifts in attention on
the attentional set-shifting task, implicating the PFC in
this dysfunction. A similar cocaine-binging protocol in
adolescents subsequently decreased anxiety and acquisition of contextual fear responses in adulthood (Sillivan
et al., 2011). Furthermore, this protocol perturbed dendritic arborization and synapses, which persisted in
adulthood. Taken together, these studies provide the first
insights into the effects of adolescent cocaine exposure on
subsequent behavior in adulthood. However, because no
adult controls (Black et al., 2006; Sillivan et al., 2011)
with binge administration of cocaine were used, the
possibility that these changes might be due to binge
administration of cocaine per se and not due to exposure
in adolescence cannot be ruled out. Nonetheless, further
studies are required to elucidate these changes.
10. Human Imaging Studies. Imaging studies
attempting to elucidate the neural mechanisms underlying cocaine addiction in humans have been of limited
scope due to a variety of reasons, including poor resolution, difficulty in quantifying the cocaine abuse history of
the participants, and problems with determining causality. However, human studies have the distinct advantage
over animal models of providing information about the
subjective effects of the drugs. These subjective effects,
nonetheless, are prone to a variety of problems. For

instance, it was recently argued that researchers studying the neural correlates of "craving" in drug addicts
might be inadvertently studying a low-level urge (Moeller
et al., 2015; Wilson and Sayette, 2015). Moreover, acute
as well as chronic cocaine intake (even after a 10-day
withdrawal period) reduces cerebral blood flow (possibly
due to vasoconstriction, because it is a sympathomimetic),
which might make the interpretation of experiments
studying glucose metabolism and blood oxygenation
(considered correlates of neural activity) more difficult
(Volkow et al., 1988; London et al., 1990; Wallace et al.,
1996). However, Gollub et al. (1998) argue that regional
changes in neuronal activity using the aforementioned
techniques can be reliably determined despite the global
reduction in blood flow. Nonetheless, one has to be careful
while drawing comparisons across studies. Another
important caveat in human brain imaging studies is the
effect of expectancy. For example, the apparent DA
release in the human NAc is significantly enhanced
[reduced binding potential of raclopride in positron
emission tomography (PET) scanning] by expectation of
receiving caffeine (Kaasinen et al., 2004). Notwithstanding these limitations, significant insights into the mechanisms underlying cocaine addiction have been achieved
using neuroimaging and neurophysiological techniques
including fMRI and PET. In cocaine-dependent individuals, intravenous infusion of cocaine induces increased
fMRI signals in the reward network of the brain,
correlating either with self-reported "rush, high, low, or
craving" (Breiter et al., 1997). Importantly, repeated
sessions reproduced the findings, but activations also
emerged in some saline infusions, which were interpreted
as expectations. The effects were registered within 100
seconds, but still the dependent individuals might have
differentiated the active drug from saline, which might
have altered the responses. However, the pharmacological effects of cocaine in the reward areas might not be
altered by expectation (Kufahl et al., 2008).
A seminal PET study revealed that the DAT occupancy by cocaine correlates with the subjective feeling of
the "high" in cocaine addicts (Volkow et al., 1997a). This
drug-induced high is negatively correlated to activity in
the NAc, OFC, and anterior cingulate cortex (Risinger
et al., 2005). Cocaine addicts have lower levels of DA
receptors in the striatum than controls, when assessed
using PET after 1 week of abstinence. However, 1 month
of abstinence is sufficient to return the receptors to
normal levels (Volkow et al., 1990). Furthermore, acute
exposure to methylphenidate, a DAT blocker like cocaine (and a drug that is reported to produce a similar
high as cocaine in addicts), demonstrates a reduced
release of DA in the striatum in cocaine addicts, even
after extended withdrawal (Volkow et al., 1997b; Martinez
et al., 2004;). Moreover, Gu et al. (2010), using fMRI, found
that resting state functional connectivity between the
VTA and NAc was negatively correlated to years of
cocaine use, further implicating a downregulation in

Drug-Induced Neuroplasticity

DAergic signaling in cocaine addicts. Studies in macaques

extend these findings by demonstrating that chronic
cocaine SA per se reduces D2Rs, which might contribute
to increased drug use (reviewed in Nader and Czoty, 2005;
Nader et al., 2006). In human cocaine addicts, D2Rs are
reduced in several regions of the frontal cortex (FC,
particularly the OFC and cingulate gyri), which is
apparent even after 34 months of abstinence (Volkow
et al., 1993). Similarly, the anterior cingulate cortex, along
with the OFC and dorsolateral PFC, is hypoactive in
response to rewarded drug cue-reactivity task (Goldstein
et al., 2009). This deficit is reversed by oral methylphenidate and is not a consequence of reduced motivation or
impaired behavioral responses, because these were controlled for in the experiments (Goldstein et al., 2009,
2010). Intriguingly, acute exposure to methylphenidate,
presumably by raising DA levels, increases metabolism in
the OFC and mPFC of cocaine addicts but not controls
(Volkow et al., 2005). Nonetheless, cocaine abusers (active
or abstinent) exhibit reduced signaling via D2/3 receptors
compared with controls on exposure to methylphenidate
(Volkow et al., 2014). Taken together, these findings
indicate that cocaine abuse results in persistently reduced
DA release, reduced DA receptor signaling, and hypoactive striatal and frontal circuits.
Strikingly, although chronic cocaine users exhibit
reduced cerebral blood flow on withdrawal as discussed
(Volkow et al., 1988), after 1 week of withdrawal,
increased global brain glucose metabolism and also
regional increases in the basal ganglia and OFC are
observed, which subside in 24 weeks (Volkow et al.,
1991). Further studies are required to understand these
differences.
As highlighted earlier, recent work has challenged the
construct validity of experiments studying craving in
addiction (Moeller et al., 2015; Wilson and Sayette, 2015).
Nonetheless, a study employing PET reported increased
cerebral blood flow to limbic regions (including the
amygdala and anterior cingulate gyri) and decreased
blood flow to the basal ganglia on cue-induced cocaine
craving compared with controls (Childress et al., 1999).
These findings were corroborated by fMRI studies, which
demonstrate increased cingulate and low frontal lobe
activation in cocaine addicts on exposure to cocaineassociated cues (Maas et al., 1998; Wexler et al., 2001).
Risinger et al. (2005) studied cocaine SA by
nontreatment-seeking cocaine addicts. Simultaneously
with SA-associated behavioral ratings they also had the
subjects scanned with fMRI. Craving was positively
correlated with activity in the NAc, OFC, and anterior
cingulate cortices, whereas cocaine-induced high was
negatively correlated with the activity in these regions,
stressing the altered states of the reward circuitry in
cocaine-related subjective states.
11. Limited Evidence of Cocaine Neurotoxicity.
In humans, PET studies have reported decreased blood
flow and frontal cortical glucose metabolism as well as

899

decreased D2 receptor availability in cocaine users

compared with control subjects. These changes were
sustained up to 4 months of abstinence (Volkow et al.,
1988, 1992, 1993). Cocaine users also displayed an
attenuation of the increase in extracellular striatal DA
levels but a greater increase in thalamic DA levels
compared with control subjects in response to a methylphenidate challenge (Volkow et al., 1997b). Studies
employing SPECT and MRI have reported changes in
regional cerebral blood flow and blood oxygen level
dependent (BOLD) signal intensity in cocaine users
while performing cognitive tests measuring memory
and executive functions. Alterations have been observed in cortical regions, the globus pallidus, putamen,
cingulate, hippocampus, and amygdala, but are not
always associated with decreased task performance
(Ernst et al., 2000; Bolla et al., 2003; Hester and
Garavan, 2004; Tomasi et al., 2007; Moeller et al.,
2010). Importantly, these studies are subject to the
same limitations (discussed in more detail in section II.
B on amphetamines) that limit the conclusions that can
be drawn from them.
Unlike amphetamines (see section II.B), the evidence
of cocaine neurotoxicity in animal models is more
limited. In rodents, cocaine does not produce any longterm depletion of DA, 5-HT, or their metabolites in
brain regions normally affected by amphetamines, such
as the striatum, cortex, hypothalamus, and hippocampus (Kleven et al., 1988; Yeh and De Souza, 1991). Other
markers of monoamine system integrity, such as monoamine transporter levels, are likewise unaffected by
binge cocaine treatments. In studies employing silver
staining, even very high-dose, multiday treatments
with cocaine up to 450 mg/kg per day failed to produce
any evidence of axonal degeneration in the striatum,
cortex, or other regions (Ryan et al., 1988; Benmansour
et al., 1992; Goodman and Sloviter, 1993). Even treatment at high ambient temperatures, an exacerbating
factor in amphetamine toxicity, did not result in any
cocaine neurotoxicity (Cappon et al., 1998).
Although widespread toxicity is generally not observed, axonal degeneration after cocaine binge treatments has been reported in one specific region
extending from the Hb toward the VTA (Ellison,
1992). The neurodegeneration in this region is not
specific to cocaine, however, and has been reported
across a wide range of stimulant drugs and also
nicotine. Interestingly, this degeneration has been
implicated to play a role in the loss of forebrain control
circuitry and development of behaviors related to binge
drug use and relapse (Carlson et al., 2000; Ellison,
2002). The activation of LHb activates the "tail" region
of the VTA, which is the rostromedial tegmental nucleus
(rmTg) (Jhou et al., 2009a). Screening of the effects of
many pharmacological agents on the GABAergic cells of
the rmTg has been carried out by monitoring the
induction of c-Fos or DFosB expression in acute

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Korpi et al.

experiments (Perrotti et al., 2005; Kaufling et al., 2010).

The robust activation of these neurons was only shared
by stimulant drugs, including cocaine, amphetamines,
methylphenidate, and caffeine, and by a DAT blocker,
but not by SERT or NET blockers, indicating that strong
DAergic activity was needed to activate the network
that involves the LHb. Many other groups of drugs
of abuse do not strongly activate the neurons in the
rmTg (Fig. 1), including morphine, ethanol, diazepam,
D9-tetrahydrocannabinol, ketamine, and phencyclidine
(Perrotti et al., 2005; Kaufling et al., 2010). Nicotine
preferentially activates, and degenerates at high doses,
the medial habenula-interpeduncular (MHb-IPN) pathway after subchronic administration (Carlson et al.,
2001; Ciani et al., 2005) (see Fig. 10), but it also acutely
excites the rmTg neurons in anesthetized rats (Lecca
et al., 2011).
12. Potential Mechanisms in Cocaine Neurotoxicity
and Neuroprotection. Some data suggest that, under
some circumstances, cocaine can function as a stressor
or as a neuroprotective agent. In cultured fetal mesencephalic DA neurons, a 5-day cocaine treatment (1025
and 1024 M) produced no effect on levels of TH-positive
cells or high-affinity [3H]DA uptake (Bennett et al.,
1993). However, other studies employing PC12 cells
found that cocaine treatment produced DNA fragmentation, cytotoxicity, decreases in Bcl-2, and increases in
caspase-3 levels (Gramage et al., 2008; Lepsch et al.,
2009). Furthermore, the cocaine metabolite benzoylecgonine has been reported to be cytotoxic (Lin and
Leskawa, 1994). Oxidative stress has been implicated
in cocaine toxicity. In vitro, cocaine toxicity can be
attenuated by application of the superoxide dismutasemimetic tempol (Numa et al., 2011), and in vivo high
doses of cocaine lead to increased levels of oxidative
stress, hydrogen peroxide, and lipid peroxidation in the
striatum and HC of rats for up to 2 days after treatment.
However, these changes coincide with increases in
levels of glutathione peroxidase and superoxide dismutase, suggesting that compensatory mechanisms may
prevent extensive long-term damage (Dietrich et al.,
2005; Numa et al., 2008). Oxidative stress may be further
increased due to cocaines reported effects on mitochondria, which include decreases in levels of complex I
subunit gene expression and membrane depolarization
(Dietrich et al., 2004; Cunha-Oliveira et al., 2006). These
and other factors that have been implicated in cocaine
toxicity, such as effects on the glutamatergic system,
neurogenesis, neuroinflammation, and blood-brain barrier permeability are discussed above and reviewed in
more detail elsewhere (Goncalves et al., 2014).
Cocaine purchased by consumers commonly contains
adulterants such as levamisole that, together with its
major metabolite aminorex, are also pharmacologically
active. Although levamisole is only a rather weak reuptake inhibitor, the metabolite aminorex was found to
exert strong reuptake inhibiting and releasing properties

similar to amphetamine (Hofmaier et al., 2014). Aminorex was previously reported to not produce any longlasting depletion of brain monoamines (Zheng et al.,
1997), but the potential toxicity of these and other cocaine
adulterants, particularly in combination with cocaine, is
a topic of interest for harm reduction requiring further
investigation.
Aside from possible toxic effects, it is interesting to
note that cocaine actually appears to protect against
toxicity of amphetamines. This effect has been linked to
the reduction of cellular uptake of the amphetamines
after cocaine, for instance due to translocation of DAT
from the plasma membrane to endosomes (Daza-Losada
et al., 2008; Peraile et al., 2010).
13. Methylphenidate and Novel Psychoactive Substances.
Aside from cocaine, there are several drugs in clinical
and recreational use that have a very similar mechanism of action. Most important in this regard is
methylphenidate. As with cocaine, there are reports of
increased oxidative stress and lipid peroxidation in
certain brain regions after methylphenidate, whereas
long-term depletion of monoamine levels is not observed
(Yuan et al., 1997; Schmitz et al., 2012; Comim et al.,
2014). Analogous with cocaine, methylphenidate also
protects against toxicity of amphetamines, and it has
been suggested it may also be protective against the
neurodegenerative processes occurring in Parkinsons
disease (Volz, 2008).
During the increase in novel psychoactive substance
use in recent years, one of the compounds that became
very widely used was 3,4-methylenedioxypyrovalerone,
a compound structurally related to amphetamines, but
with more extensive substitutions, including an extended carbon chain instead of a methyl group at the
a-carbon. Hence, the drug does not function as a transporter substrate but, like cocaine, strongly inhibits
monoamine reuptake. It is most potent at the DAT
and NET and to a lesser extent at the SERT (Baumann
et al., 2013; Cameron et al., 2013; Iversen et al., 2014). A
further investigation of the potential neurotoxic and
neuroprotective effects of 3,4-methylenedioxypyrovalerone and similar novel compounds, e.g., mephedrone,
could be of interest.
14. Conclusions. Basic research on cocaine has produced a large amount of detailed neurobiological,
molecular biologic, and gene regulation data (for a summary, see Fig. 7), which help to understand the biologic
background of various phases of cocaine addiction in
different reward/emotion/cognition-related brain regions.
Unfortunately, this vast database has not yet produced
enough translational results to treat cocaine-addicted
patients.
B. Amphetamine-type Psychostimulants
DA plays an important role in reward and motivation,
two aspects of behavior, which are central to goaldirected behavior for both human as well as nonhuman

Drug-Induced Neuroplasticity

animals (Salamone, 1994; Koob, 1996). Reward can be

viewed as the subjective pleasurable sensation associated with fulfilling a physiologic need, such as quenching hunger or thirst with food or water, whereas
motivation is the subsequent willingness to exert effort
in performing goal-directed behavior to achieve these
rewards. The mesolimbic DA system, consisting of
projections from the VTA to the NAc plays an important
role in mediating reward and motivation (Wise, 2006)
(Fig. 1). Recreational drug use is also associated with
pleasurable sensations (Fischman and Foltin, 1991). So
it should come as no surprise that all drugs that produce
these sensations also produce increases in the DA

901

neurotransmission in the NAc in a similar, but more

robust, way as do natural or physiologically important
rewarding stimuli (Wise and Rompre, 1989). Amphetamines such as AMPH and METH are particularly
interesting in this respect as they, unlike other more
indirectly acting drugs, except for cocaine, preferentially increase DA levels in the NAc (Wise and Rompre,
1989) via several mechanisms described below (Fig. 5;
Table 1).
As will be described in more detail in the rest of this
section, the primary effect of amphetamines is to increase monoamine neurotransmission by inhibiting the
reuptake and enhancing the release of the monoamines

Fig. 7. Summary of main neuroplasticity-related changes observed in selected brain regions during different stages of cocaine addiction. The colored
arrows indicate the stages of addiction depicted inside the arrows.

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Korpi et al.

DA, NE, and 5-HT through the DAT. However, AMPH

also affects secretory vesicles, enzymes involved in DA
biogenesis and metabolism, and many other targets.
AMPH-type stimulants have been employed for a long
time, both for medical and recreational purposes. This
raises the question of what, other than its initial effects
on brain neurochemistry, the long-term effects AMPH
exposure may produce.
1. Many Stimulant Amphetamines for Abuse and
Therapy. The biggest and most diverse group of
psychostimulants is the amphetamines. In its most
basic form, amphetamine (AMPH), a contraction of
a-methyl-phenethylamine, consists of a phenyl ring
connected to an amino group by a two-carbon side chain
with a methyl group on carbon 1. The addition of
a methyl group on the nitrogen atom produces methamphetamine (METH). Various other ring and side
chain substitutions produce other well-known amphetamine analogs such as methylphenidate (MPH) and
3,4-methylenedioxymethamphetamine (MDMA, ecstasy).
We will focus here on the amphetamines in general and
make notes on specific qualities of individual compounds as necessary. The amphetamines all exist as
isomers with subtle differences in their neurochemical
and behavioral properties. For AMPH, the d-isomer
appears to be a more potent DA releaser, whereas the
l-isomer is an equally or more potent releaser of NE
(Heikkila et al., 1975; Holmes and Rutledge, 1976;
Mendelson et al., 2006). Furthermore, the d-isomers
of AMPH and METH appear more potent than the
l-isomers in producing behavioral effects such as locomotor activity, SA, and taste aversion (Balster and
Schuster, 1973; Yokel and Pickens, 1973; Carey and
Goodall, 1974; Segal, 1975). Illicit METH is usually
distributed as either a racemic mixture of d- and
l-isomers or as pure d-isomer, depending on the method
of synthesis most prevalent at the time (Logan, 2002;
Mendelson et al., 2006).
Psychostimulants have been widely used medically
(Iversen, 2006), but presently their therapeutic use is
more limited. AMPH and MPH are the first line treatment of attention deficit hyperactivity disorder (ADHD),
a common disorder primarily characterized by decreased
impulse control and attention, affecting approximately
4% of the population (Surman et al., 2013). They are also
used for management of narcolepsy (De la Herran-Arita
and Garcia-Garcia, 2013). Furthermore, although not
currently approved, recent clinical trials have provided
evidence that MDMA may be effective in the treatment of
otherwise treatment-resistant anxiety disorders (Mithoefer
et al., 2011, 2013). Recreational use of amphetamines,
particularly AMPH, METH, MDMA, and more recently,
various b-ketoamphetamines is also widespread, with
amphetamine-type stimulants being the worlds second
most consumed illegal drugs after cannabis (UNODC,
2011). Like other psychostimulants such as cocaine, the
subjective effects of amphetamines are associated with

increases in DA and include euphoria, increased energy,

insomnia, and decreased appetite. However, excessive
DA stimulation can also lead to amphetamine psychosis,
a condition that shows strong similarity to the psychotic
episodes experienced by patients suffering from schizophrenia and which constitutes one of the primary reasons
for amphetamine-related hospitalization (Snyder, 1973;
McKetin et al., 2013; Medhus et al., 2013).
2. Molecular Targets and Mechanisms of Action of
Amphetamines. Historically, the mechanisms that
have received the most attention are the ability of
amphetamines to inhibit the reuptake and enhance
the release of DA via the DAT, as well as their ability to
promote the release of DA from secretory vesicles
(Sulzer et al., 2005; Fleckenstein et al., 2007)(Fig. 5).
Recently, it has become clear that, aside from these
traditional mechanisms, amphetamines are also capable of modulating action potential-dependent neurotransmitter release (Branch and Beckstead, 2012;
Daberkow et al., 2013). Furthermore, amphetamines
regulate DA neurotransmission via inhibition of monoamine oxidase (MAO) and enhancement of tyrosine
hydroxylase (TH) and have numerous other receptor
targets, including the a2-adrenergic receptor, the sigma
receptor, and the trace amine-associated receptor 1
(TA1) receptor (Fung and Uretsky, 1982; Robinson,
1985; Ritz and Kuhar, 1989; Matsumoto et al., 2014;
Reese et al., 2014). Many of these targets have been
identified only recently, and their importance in mediating the effects of amphetamines on behavior as well as
its therapeutic, reinforcing, and toxic effects are just
beginning to be understood.
3. Comparison of the Mechanisms of Action of
Amphetamine versus Methamphetamine. It is sometimes stated that METH is more addictive and more
powerful than AMPH, but this statement has been hard
to back up empirically. The changes in extracellular DA
levels measured by microdialysis in rats are correlated to
the striatal drug levels and are equal for the d-isomers of
both drugs (Melega et al., 1995). One study confirmed
that d-AMPH and d-METH produce similar increases in
NAc DA levels in rats and actually found that AMPH
increases PFC DA levels more than METH and also
produces a higher peak locomotor activity (Shoblock et al.,
2003b). In line with the effect on PFC DA levels, it was
discovered that AMPH has a stronger effect than METH
on working memory function. The effects of AMPH and
METH on working memory are bimodal, with a small
dose producing an increase in working memory performance and higher doses producing a decrease, an effect
closely reminiscent of the bimodal effects of DA turnover
and D1 receptor activation on working memory (Murphy
et al., 1996; Vijayraghavan et al., 2007). For d-AMPH,
a dose of 0.5 mg/kg produces an increase in working
memory performance, whereas a 2 mg/kg dose produces
a decrease. d-METH on the other hand has little effect at
0.5 mg/kg, producing the highest increase at 2 mg/kg and

Drug-Induced Neuroplasticity

only decreasing at 4 mg/kg (Shoblock et al., 2003a).

Furthermore, d-AMPH fully substitutes for d-METH in
animals trained to discriminate METH from placebo
(Desai and Bergman, 2010) and also causes dosedependent increases in METH-appropriate responding
in humans who have learned to discriminate 10 mg
METH from placebo (Sevak et al., 2009), suggesting that
the subjective effects are also very similar, if not indistinguishable. Recently, it was also shown that varying
doses (between 12 and 50 mg intranasally) of d-AMPH or
METH produce similar subjective effects and did not
differ from each other with regards to the rate at which
participants would opt for a cash reward instead of a dose
of the drug (Kirkpatrick et al., 2012), thereby not
corroborating the notion that METH is more addictive
or reinforcing than d-AMPH.
By tradition, scientific work on the mechanism of
action of amphetamines has been primarily done with
AMPH, whereas studies on neurodegeneration preferentially have employed METH (Sulzer et al., 2005).
4. Effects of Amphetamine at Plasmalemmal Dopamine Transporter. The DAT as well as the other
monoamine transporters, NET and SERT, belong to
the SLC6 gene family of secondary active transporters
consisting of 12 transmembrane domains as well as
intracellular domains with phosphorylation and binding sites vital for its regulation, including by AMPH.
Normally, the transporters depend on pre-existing
concentration gradients of Na+ and Cl2 to cotransport
one molecule of Na+ together with one neurotransmitter
molecule from the extracellular space into the cytoplasm (Robertson et al., 2009).
The ability of AMPH to increase extracellular DA
levels in vivo is well established, and one area particularly sensitive to AMPH-induced increases in extracellular DA is the NAc (Carboni et al., 1989). AMPH blocks the
reuptake of DA via the DAT (Parker and Cubeddu, 1988).
However, intracytoplasmic injections of AMPH also increase extracellular DA, and this effect is blocked by the
DAT blocking drug nomifensine, indicating that AMPH,
aside from blocking the reuptake, also enhances the
release of intracellular DA (Sulzer et al., 1995). The
uptake of radiolabeled AMPH into striatal synaptosomes
is a saturable and high-affinity process that is sensitive to
ouabain and cocaine and dependent on temperature,
suggesting that AMPH is itself a substrate of the DAT
(Sitte et al., 1998; Zaczek et al., 1991). In addition, it is
important to note that AMPH is a lipophilic weak base
(Mack and Bonisch, 1979; Gulaboski et al., 2007), which
will, particularly at higher concentrations, diffuse
through the plasma membrane and enter the cytoplasm
independently of the DAT.
An early model (Fischer and Cho, 1979) known as the
exchange-diffusion model, postulated that AMPH, like
DA, would bind to an extracellular binding site, causing
a conformational change in the DAT protein resulting in
the binding site traversing the membrane and releasing

903

AMPH into the cytoplasm and simultaneously binding

a DA molecule to be transported outward. Later it would
become clear that this exchange-diffusion is not limited
to a 1:1 ratio of AMPH exchange for DA. AMPH also
increases intracellular levels of Na+, and increases in
Na+ are in itself sufficient to induce release of DA via the
DAT; it is likely that it is the influx of Na+ ions via the
DAT rather than AMPH itself that triggers reverse
transport of DA. Furthermore, the DAT can be regulated, as discussed below, via intracellular second
messengers between reluctant and willing states
for AMPH-mediated DA efflux without affecting inward
transport (Khoshbouei et al., 2004). AMPH is also be
capable of producing rapid bursts of DA release via the
DAT, which is indicative of AMPH causing a conformational change to the DAT resulting in a channel-like
state in which DA is rapidly transported outward via
a pore in the transporter protein. The process is
transient, consisting of millisecond bursts and is
inhibited by the presence of DA on both sides of the
plasma membrane and therefore not capable of transporting DA against its concentration gradient (Kahlig
et al., 2005). Finally, recent evidence suggests that
AMPH also affects the DA release associated with
action potentials. One study that examined this demonstrated that AMPH at 10 mg/kg enhanced electrically
evoked DA release measured 10 and 30 minutes after
the initial injection. Additionally, it was shown that
a low dose (1 mg/kg) of AMPH facilitated the DA release
associated with a rewarding stimulus cue, suggesting
that AMPH acts, at least in part, by altering the
characteristics of action potential-dependent exocytotic
DA release (Daberkow et al., 2013). Unlike AMPH, MPH
was recently shown to decrease exocytotic DA release
(Federici et al., 2014), which may help explain the
differing subjective effects of this drug. The exact mechanism by which AMPH increases the exocytotic release of
DA is unknown, but may be related to the ability of
AMPH to induce persistent transporter-mediated ionleakage and excitatory conductance (Ingram et al., 2002;
Branch and Beckstead, 2012; Rodriguez-Menchaca et al.,
2012). It has been suggested that reuptake inhibition is
primarily associated with lower drug concentrations,
possibly corresponding to those in the therapeutic range,
whereas doses in the recreational range shift the importance to AMPH-mediated DA release (Calipari and
Ferris, 2013). Furthermore, there appear to be regionspecific changes in the relative importance of DATdependent and action potential-dependent DA release,
with enhancement of vesicular release being more important in the dorsal striatum compared with the ventral
striatum (Avelar et al., 2013). As discussed further
below, the final increases in cortical and NAc DA levels
mediate both the therapeutic and reinforcing effects of
amphetamines.
5. Regulation of Dopamine Efflux Via the Dopamine
Transporter by Protein Kinase C and Ca2+/Calmodulin

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Kinase II Phosphorylation, and by Reactive Oxygen

Species. The release of DA via the DAT is highly
dependent on DAT expression on the surface of the
plasma membrane and is regulated by several intracellular second-messenger systems. Phosphorylation by
PKC plays an important role in regulation of DAT
function and surface expression. PKC-activating and
phosphatase-inhibiting drugs both decrease the uptake
of DA into striatal synaptosomes in vitro. The effect is
inhibited by the PKC inhibitor staurosporine (Copeland
et al., 1996; Zhang et al., 1997). Studies in striatal
synaptosomes employing [32P]orthophosphate to assess
the amount of DAT phosphorylation confirmed that
phosphorylation at DAT is regulated by PKC and that
the amount of DAT phosphorylation is directly related
to the efficacy of DA uptake, with increased phosphorylation decreasing the uptake efficacy (Vaughan et al.,
1997). PKC activation removes DAT from the membrane to endosomes, whereas PKC inhibition promotes
the insertion of DAT into the membrane, something
that has been confirmed using immunofluorescence
confocal microscopy (Pristupa et al., 1998; Sorkina
et al., 2003). In addition to affecting DA uptake, PKCmediated DAT phosphorylation also affects AMPHinduced DA release. One study found that PKC-inhibiting
drugs almost completely inhibited AMPH-induced DA
efflux, while increasing baseline DA uptake in the
absence of AMPH (Kantor and Gnegy, 1998). The effect
of PKC-mediated DAT phosphorylation on AMPHinduced DA release appears to be mediated specifically
by the PKCbII isoform (Johnson et al., 2005). Thus,
whereas increases in phosphorylation appear to decrease the efficacy of baseline DA uptake and decrease
cell surface DAT expression, the opposite appears to be
the case for AMPH-mediated DA efflux, which is reduced by inhibition of phosphorylation.
METH is capable of inducing DAT phosphorylation
both in vivo and in vitro (Cervinski et al., 2005). A single
in vivo injection of METH rapidly (within 1 hour) and
reversibly decreased plasmalemmal DA uptake,
whereas the total binding of the membrane-permeable
DAT ligand WIN35428 was not affected, indicative of
METH-induced transient transporter internalization or
loss of function (Fleckenstein et al., 1997b; Kokoshka
et al., 1998; Saunders et al., 2000). These data suggest
that AMPH produces transporter internalization in
a similar way as does PKC activation. However, there
appear to be subtle differences between PKC-dependent
and AMPH-dependent DAT internalization. Both AMPH
and PKC activation results in loss of cell surface DAT in
vitro, but contrary to the PKC-induced internalization
that is dependent on DAT ubiquitination and subsequent
sorting to LAMP1-positive endosomes for degradation,
the AMPH-induced internalization sorted the DAT to
Rab11-positive recycling endosomes (Hong and Amara,
2013), likely destined to be quickly reinserted into the
membrane.

AMPH-mediated DA efflux appears to be influenced

also by CaMKIIa. CaMKIIa binds the DAT at the
distant C terminus while inducing phosphorylation at
similar residues as PKC, namely the N-terminal serines. Phosphorylation by this kinase increases AMPHinduced DA efflux via DAT, and mutations at both the
C-terminal binding site as well as the N-terminal
phosphorylation sites inhibit the increase (Fog et al.,
2006). CaMKII appears to influence AMPH-mediated
DA efflux via the DAT through Syntaxin A1, a protein
that, aside from being involved in synaptic vesicle
release, interacts with and regulates transmembrane
proteins, including DAT (Binda et al., 2008; Robertson
et al., 2009). Interestingly, association of Syntaxin A1
with the DAT is also subject to regulation by AMPH
itself (Binda et al., 2008), pointing to another target by
which AMPH itself regulates AMPH-dependent, DATmediated DA efflux.
There is also evidence suggesting that ROS signaling
may be involved in regulating cell surface DAT expression (Fleckenstein et al., 2007). The oxygen radicalgenerating enzyme xanthine oxidase reduces DA
uptake into striatal synaptosomes, an effect inhibited
by coapplication of the free radical scavenger superoxide dismutase (Berman et al., 1996; Fleckenstein et al.,
1997a). As discussed in more detail below, AMPH is also
capable of generating ROS, so this regulatory pathway
is also open to modulation by AMPH itself.
Regulation of DAT function via phosphorylation and
ROS are some mechanisms by which DAT surface
expression and function is regulated. Because these
mechanisms are affected by the presence of AMPH
itself, it appears that the final amount of DA released
into the extracellular space in response to AMPH
depends on a complex interplay between AMPH and
intracellular second-messenger systems, some of which
may not have been discovered yet. To add to this
complexity, AMPH also affects the amount of DA available for release via several mechanisms by affecting DA
sequestration in secretory vesicles.
6. Effects on Secretory Vesicles. In addition to releasing DA from the cytoplasm to the extracellular
space, AMPH also promotes the release of DA from
secretory vesicles. Several mechanisms by which
AMPH may release DA from secretory vesicles into
the cytoplasm have been suggested, including AMPH
weak base effects, competition at the vesicular monoamine transporter 2 (VMAT-2), and redistribution of
VMAT-2.
AMPH is a lipophilic weak base (Gulaboski et al.,
2007; Mack and Bonisch, 1979) and, as such, is capable
of traversing the membranes of synaptic vesicles. The
lumen of secretory vesicles is acidic, with a pH of around
5.5 (Mellman et al., 1986; Njus et al., 1986), and once
inside the vesicle lumen AMPH is protonated, decreasing its membrane permeability and leading to accumulation of AMPH inside the vesicles. The protonation of

Drug-Induced Neuroplasticity

AMPH also leads to a loss of the proton gradient

established by H+-ATPase across the vesicular membrane, which is required by the secondary active transporter VMAT-2 to sequester DA into the vesicles,
eventually leading to DA release into the cytoplasm
(Sulzer and Rayport, 1990; Sulzer et al., 2005). The loss
of DA from secretory vesicles leads to a decrease in
quantal size due to the lower amount of DA in individual
vesicles. However, after prolonged (648 hours) exposure to METH a rebound hyperacidification and subsequent increase in quantal size has been reported
(Markov et al., 2008), indicative of a homeostatic mechanism capable of preventing long-term loss of DA from
secretory vesicles.
In addition to promoting release by interfering with
the membrane proton gradient, AMPH also has affinity
for VMAT-2 itself, suggesting it may also interfere with
the uptake of DA into vesicles and cause a net decrease
of vesicle neurotransmitter content (Sulzer et al., 2005).
Finally, repeated high-dose METH treatment decreases
vesicular DA uptake without affecting total binding of
the VMAT-2 ligand [3H]dihydrotetrabenazine, consistent with removal of VMAT-2 from the vesicular
membrane (Brown et al., 2000; Hogan et al., 2000).
However, due to the relatively low affinity of AMPH for
VMAT-2 (see Table 1), the importance of VMAT-2dependent mechanisms in affecting AMPH-induced
vesicular DA efflux at physiologically relevant concentrations has been questioned (Gonzalez et al., 1994;
Fleckenstein et al., 2007).
7. Other Amphetamine Targets: Monoamine Oxidase,
Tyrosine Hydroxylase, other Monoamine Transporters,
Trace Amine-Associated Receptor 1, and Sigma
Receptors. The ability of AMPH to block MAO has
been repeatedly demonstrated both in vitro and in vivo
(Mantle et al., 1976; Green and el Hait, 1978; Clarke
et al., 1979; Miller et al., 1980; Robinson, 1985). AMPH
also increases DA levels because of enhancement of TH
function (Costa et al., 1972; Kuczenski, 1975), although
high concentrations appear to decrease TH function
(Kogan et al., 1976; Hotchkiss and Gibb, 1980). The
exact mechanism by which AMPH increases TH function is not known (Sulzer et al., 2005). This highlights
that AMPH, at least to a certain extent, compensates for
its enhancement of DA efflux by increasing cellular DA
levels by inhibiting DA breakdown and increasing DA
biosynthesis.
AMPH also increases extracellular levels of 5-HT and
NE (Kuczenski and Segal, 1997) in a similar fashion by
inhibiting the reuptake and enhancing the release of
these neurotransmitters via their respective plasmalemmal transporters (Parada et al., 1988; Rothman
et al., 2001; Hilber et al., 2005). The effects of AMPH
in these other monoamine systems play an important
role in mediating part of its behavioral effects (Xu et al.,
2000; Gingrich and Hen, 2001; Gainetdinov et al., 2002;
Perona et al., 2008).

905

Several other targets for AMPH and METH are

known. Recently the TA1 (Reese et al., 2014) and sigma
receptors (Matsumoto et al., 2014) have received attention. The TA1 is a trace amine-associated GPCR and
colocalizes with DAT in certain brain regions. It exerts
a modulatory effect on monoamine neurotransmission
(Xie and Miller, 2009). Taar1-KO mice show clear
behavioral differences and respond more strongly to
the locomotor activating and rewarding effects of
AMPH (Achat-Mendes et al., 2012a). The sigma receptor, a one-transmembrane domain receptor at the
endoplasmic reticulum (ER) encoded by the SIGMAR1
gene that is involved in cellular Ca2+ and K+ regulation
(Aydar et al., 2002; Monassier and Bousquet, 2002), is
another interesting target in mediating METH neurotoxicity. METH preferentially binds to the s1 over the s2
subtype, and blocking the receptor acutely decreases
the drugs locomotor stimulating effects (Hayashi and
Su, 2007). Sigma receptor blockade also attenuates
striatal DA depletion, cytokine activation, and cognitive
impairment induced by high-dose METH treatment in
rodent models, something that may be related to its
effects on cellular Ca2+ levels or the expression of s
receptors on microglia (Robson et al., 2013a,b; Seminerio et al., 2013).
For AMPH and METH, the DA system is clearly
important in mediating its neurochemical and behavioral effects, although it is clear that some of its effects
are also mediated by different neurotransmitter systems, some of which only recently have been identified.
8. Action of Substituted Amphetamines and
Cathinones. Once the amphetamine molecule is subjected to substitutions, its properties change in important ways. The substituted amphetamines MDMA and
the cathinones mephedrone (4-MMC) and methylone
(MDMC) have a mechanism of action that is reminiscent of AMPH and METH but they differ in the ratio of
their effects at various monoamine systems (Table 1).
AMPH and METH bind to DAT, NET, and SERT, but
they show a strong preference for the catecholamine
transporters DAT and NET and have much lower
affinity for the SERT (Nichols, 1994; Simmler et al.,
2013). Subsequently, their main effect in vivo is to
increase extracellular DA levels in the NAc and FC
without having strong effects on 5-HT release (Carboni
et al., 1989; Kehr et al., 2011; Melega et al., 1995;
Shoblock et al., 2003b).
Substitutions of the phenyl ring on the amphetamine
molecule produce compounds with much higher affinity
for SERT, although they often maintain DA-releasing
properties as well (Nichols, 1994). Thus, MDMA, which
contains a 3,4-methylenedioxy substitution, is a potent
5-HT-releasing agent with relatively weak effects on
DAT (Cozzi et al., 1999; Verrico et al., 2007; Simmler
et al., 2013). Furthermore, like AMPH and METH,
MDMA also induces neurotransmitter efflux from synaptic vesicles (Rudnick and Wall, 1992; Mlinar and

906

Korpi et al.

Corradetti, 2003). In vivo, it produces increases in NAc

levels of 5-HT and DA, with 5-HT levels generally
increasing more than DA (Kehr et al., 2011; Baumann
et al., 2012).
The cathinones 4-MMC and MDMC, also called
b-ketoamphetamines because of the ketone moiety on
the b-carbon, have similar affinity for plasmalemmal
monoamine transporters as their nonketoamphetamine
parent compounds but display a more than 10-fold
lower affinity for the VMAT-2 (Cozzi et al., 1999;
Baumann et al., 2012; Martinez-Clemente et al.,
2012). The exact importance of the lower VMAT-2
affinity is currently unknown, but because 4-MMC is
also a weak base (Santali et al., 2011), it is likely that it
is also capable of inducing neurotransmitter efflux from
secretory vesicles in a similar way as other amphetamines. In vivo, 4-MMC produces an effect somewhere
in between MDMA and AMPH, producing large
increases in both DA and 5-HT levels in the NAc,
whereas MDMC produces a neurotransmitter release
pattern similar to but slightly weaker than MDMA,
increasing primarily 5-HT levels (Kehr et al., 2011;
Baumann et al., 2012; Wright et al., 2012). So, although
the mechanism of action of these ring-substituted
compounds is similar to that of AMPH and METH, they
all share the property of being capable of producing
large increases in extracellular 5-HT levels in addition
to affecting extracellular catecholamine levels to varying extents.
9. Action of Stimulants Common in Clinical Use.
In addition to AMPH and METH, the drug MPH as well
as the AMPH prodrug lisdexamfetamine (LDX) is used
for the treatment of ADHD.
MPH is, because of the loss of its a-methyl moiety, by
chemical definition not an amphetamine. Nonetheless it
is a stimulant drug and has been the mainstay of
ADHD-treatment for several decades (Patrick and
Markowitz, 1997). The action of MPH shows some
similarity to AMPH and also produces an increase of
striatal DA levels in vivo, measured using microdialysis
(Aoyama et al., 1996). Studies in membrane fractions
and synaptosomes show that MPH, like AMPH, inhibits
the reuptake of the catecholamines by DAT and NET
but has little affinity for SERT (Schweri et al., 1985;
Gatley et al., 1996). In contrast to AMPH, however,
MPH appears to function primarily as a reuptake
blocker and not as a releasing agent (Braestrup, 1977;
Patrick et al., 1987).
LDX is a prodrug consisting of AMPH covalently
bound to the amino acid lysine. As a prodrug it is
inactive until it is enzymatically cleaved into lysine and
free AMPH. LDX does not appear to be very lipophilic,
and enzymatic cleavage by hydrolysis occurs only after
peptide carrier-mediated absorption in the small intestine (Pennick, 2010). The prodrug formulation has
been suggested to be a clinical improvement over
regular AMPH because it is longer lasting and thus

allows for once daily dosing as well as possibly limiting

its potential for nonmedical use (Goodman, 2007). A
study investigating the effect of LDX and AMPH (both
1.5 mg/kg AMPH base) indeed shows that the onset of
increases in striatal DA levels is slower with LDX,
corresponding to the plasma concentration of the
AMPH metabolite rather than the prodrug. Moreover,
the plasma area under the curve for AMPH is similar for
both drugs but with LDX showing a 50% lower maximum concentration and significantly longer delay from
administration until the maximum concentration is
reached. Finally, LDX induces significantly less locomotor activity (Rowley et al., 2012).
10. Efficacy and Addiction Liability of Amphetamines in Clinical Use. The ability of amphetamines
to increase synaptic DA levels via various mechanisms
is thought to play a pivotal role in both producing their
therapeutic as well as their rewarding effects.
In ADHD patients, there is a plethora of evidence
pointing toward deficits in DA neurotransmission as
playing a key role in the pathophysiology of the disease.
As reviewed earlier (Swanson et al., 2007), several
imaging studies suggest structural abnormalities in
ADHD patients, such as decreased volumes of the DArich caudate nucleus and its target globus pallidus. This is
consistent with fMRI studies, which have reported hypoactivation of the FC as well as the frontostriatal DA
circuitry while performing tasks requiring sustained
attention. These abnormalities are resolved after treatment with psychostimulants. Functional abnormalities as
well as the symptoms observed in ADHD patients appear
to normalize after stimulant drug treatment, which
increases synaptic DA levels (Lee et al., 2005). However,
the long-term effects of stimulant treatments are still
poorly understood. Although studies generally find sustained symptom improvement, it has been harder to
demonstrate consistent improvement in standardized test
scores and ultimate educational attainment (Hechtman
et al., 2004; Loe and Feldman, 2007; Hazell, 2011).
Aside from efficacy, another interesting question is
how stimulant treatment of ADHD patients affects
addiction liability later in life. A number of studies,
including one meta-analysis, have examined this question and concluded that stimulant treatment generally
appears to lower the risk of substance abuse disorder
later in life (Wilens et al., 2003; Mannuzza et al., 2008).
This effect may be understood by considering that
impulsive behavior is one of the primary risk factors
for initiation of drug use (Kreek et al., 2005) and that
stimulant treatment effectively reduces impulsivity in
ADHD patients. On the other hand, misuse and diversion of stimulant medication has become increasingly common, and it is estimated that in the past year,
5 to 35% of college-aged individuals have used a stimulant drug not prescribed to them (Wilens et al., 2008).
MPH is another drug that elicits subjective effects
of drug-liking similar to AMPH, and the subjective

Drug-Induced Neuroplasticity

rewarding effect appears to be dependent upon

increases in synaptic DA levels produced by the drug
(Rush et al., 2001; Volkow et al., 2002; Arria and Wish,
2006; Botly et al., 2008). LDX also produces similar
feelings of subjective drug-liking on questionnaires in
human volunteers as the 50% lower doses of AMPH
base (Jasinski and Krishnan, 2009). The higher dose
need likely represents the amount needed to achieve
similar peak plasma AMPH concentrations and
increases in the NAc DA levels, which at an equimolar
ratio emerge slower and remain lower due to its
extended absorption time of LDX.
Ring substitution of amphetamines produces substances with a high capability of increasing both 5-HT
and catecholamine levels (Nichols, 1994). Some of these
compounds, most notably MDMA, appear to produce
effects that are somewhere between those of pure
stimulants and typical hallucinogens such as LSD or
psilocybin. The most important effect appears to be that
they, next to creating a feeling of euphoria and wellbeing, produce emotional opening and empathy. This
observation has led to the term empathogen or entactogen being coined to describe these substances, as well
as the suggestion that they may be valuable in the
clinics as an aid to psychotherapy (Nichols, 1986). In
fact, recent clinical trials support the idea that MDMA
may be effective when used as an aid in psychotherapy
for treating treatment-resistant posttraumatic stress
disorder patients (Mithoefer et al., 2011, 2013). The use
of MDMA and related more serotonergic amphetamines
is not usually associated with significant addiction
propensity. This is thought to be due to 5-HT receptor stimulation having antiaddictive properties
something that will also be touched on in section II.I on
hallucinogens.
11. Neuroplasticity Related to Sensitization and
Addiction to Amphetamines. The incentive sensitization theory of drug addiction states that repeated drug
administration can lead to long-lasting adaptations
resulting in hypersensitivity or sensitization in parts
the mesolimbic DA system involved in processing a subcomponent of reward termed incentive salience or drug
wanting, which is thought to mediate the increased
drug seeking and taking characteristic of drug addiction. Repeated treatment with reinforcing drugs produces a gradual increase in locomotor activity after
administration, an effect known as psychomotor sensitization. Because it is assumed that the neural
adaptations responsible for developing psychomotor
sensitization are similar to those involved in producing
incentive sensitization, the former is often used as
a model for the development of addiction (Robinson
and Berridge, 2000).
Treatments with psychostimulants such as AMPH
and METH produce psychomotor sensitization associated with neuroadaptations in the VTA and NAc, but
also in the PFC, amygdala, and HC (Anagnostaras and

907

Robinson, 1996; Nestler, 2001; McDaid et al., 2006;

Perez et al., 2010; van der Veen et al., 2013). A number
of different types of structural and synaptic plasticity
have been described that may be responsible for this
effect. For example, treatment with psychostimulants,
including AMPH, result in upregulation of TH levels in
the VTA and NAc. Exposure to psychostimulants also
causes synaptic changes, such as downregulation of
inhibitory D2Rs but upregulation of excitatory D1Rs in
the VTA. It has also been suggested that NMDARs may
become more permeable to Ca2+, due to secondmessenger-mediated signaling in response to repeated
psychostimulant exposure. The ultimate result of all
these adaptations is enhanced DA neurotransmission in
the mesolimbic system, which is critical for the development of sensitization to psychostimulants (Licata and
Pierce, 2003; Kasanetz et al., 2010; Fernandez-Espejo
and Rodriguez-Espinosa, 2011). VTA NMDARs appear
to play a vital role in psychostimulant-induced neuroplasticity through activation of CaMKII. Increased Ca2+
influx after psychostimulants such as AMPH and cocaine elevate CaMKII levels, and inhibition of CaMKII
blocks both behavioral sensitization and drug-seeking
behavior (Licata et al., 2004; Loweth et al., 2008). The
importance of CaMKII signaling is also evident because
of its vital role in memory formation and because it has
been shown to be directly involved in sensitization via
activation of CREB and regulation of TH transcription
(Lim et al., 2000; Lisman et al., 2002).
Also MDMA affects sensitization and memory. A dose
of 12.5 mg MDMA administered once a week for 3 weeks
increased LTP in CA1 pyramidal neurons (hippocampal
slices) 1 week after in vivo treatment (Morini et al.,
2011), whereas an in vitro study showed that acute
MDMA increases LTP in the CA3-CA1 synapses involving the activation of presynaptic 5-HT2 and postsynaptic D1/5 receptors and was suppressed by a PKA
inhibitor (Rozas et al., 2012). Acute administration of
MDMA increased expression of c-Fos, erg-1 and erg-3 in
the striatum that was suppressed by SL327, a selective
inhibitor of ERK activation, and this effect was selective
for the striatum (Salzmann et al., 2003). Repeated
administration of MDMA, gamma-hydroxybutyrate
(GHB), and their combination results in long-lasting
changes in hippocampal protein expression even after
a washout period (van Nieuwenhuijzen et al., 2010),
whereas MDMA treatment (0.2 and 2 mg/kg) twice
a day for 6 days in young rats caused dose-dependent
impairment in spatial learning and reduced LTP (AriasCavieres et al., 2010). Furthermore, just like AMPH,
MDMA also produces sensitization after repeated exposure (Bradbury et al., 2012).
Repeated stimulant exposure that produces sensitization also results in morphologic changes to neurons in
the NAc and PFC. Both SA and noncontingent injections of cocaine (15 mg/kg) or AMPH (3 mg/kg/day)
produce an increase in the density of and the amount of

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Korpi et al.

branching of the dendritic spines on NAc MSNs and

PFC pyramidal neurons for more than 3 weeks after the
final treatment (Robinson and Kolb, 1999a; Robinson
et al., 2001). Meanwhile, METH-induced tissue plasminogen activator mRNA in a subgroup of corticostriatal neurons was suggested to contribute to the
development of lasting changes in the specific neuronal
circuits that underlie long-term behavioral modifications (Hashimoto et al., 1998). Repeated, intermittent
exposure to MDMA in rats causes behavioral sensitization and large increases in spine density and number in
the NAc (multiple-headed spines in core and shell) and
prelimbic regions (distal dendrites of layer V pyramidal
neurons) (Ball et al., 2009). Additionally, a reduction in
the basilar dendrites was observed in the anterior
cingulate. These changes accounted for the longlasting locomotor sensitization to MDMA that is accompanied by reorganization of synaptic connectivity in the
limbic-corticostriatal circuit (Ball et al., 2009). The longlasting behavioral (increased locomotion and rearing)
and EEG changes (peak at 34.5 Hz) due to MDMA
treatment were associated with DNA single- and
double-strand breaks, persistent together with longlasting metabolic changes in the hippocampal formation
(Frenzilli et al., 2007).
Protein synthesis plays an important a role in the
induction of these morphologic changes, because proteins such as c-Fos and DFosB, but also Arc, a marker of
neuritic outgrowth, and BDNF, which is involved in
spine formation, are all elevated after AMPH or cocaine
exposure (Nestler et al., 2001; Klebaur et al., 2002;
Meredith et al., 2002; Grimm et al., 2003; Fumagalli
et al., 2006). Particularly the rmTg appears to be an
important target for AMPH-induced modulation of Fos
genes that can also have strong functional and behavioral significance in terms of modulating the mesolimbic
systems through its GABAergic projections (Barrot
et al., 2012; Bourdy and Barrot, 2012) (Fig. 1). MDMA
treatment of young rats increased 2,5-dimethoxy-4iodoamphetamine (DOI)-induced energy metabolism
in the NAc and HC that reflects long-term brain
region-specific changes in plasticity, and such an effect
may result from changes 5-HT2A receptor function (Bull
et al., 2006). Likewise, a dose (12.5 mg/kg) of MDMA
increases basal Arc expression in the cortex and CA1
(Beveridge et al., 2004). DOI treatment (or immobilization stress) regulates neocortical Arc mRNA expression
through BDNF signaling (Benekareddy et al., 2013).
Chronic MDMA treatment increased NT-4 gene expression in the brain stem, cerebellum, and cerebral hemispheres of rats (Hatami et al., 2010).
Aside from changes in a number of well-characterized
proteins, AMPH treatment produces wide-ranging
changes in expression of other genes as well. A recent
study showed increased striatal mRNA expression of 55
genes, whereas 17 genes were downregulated after
a 5-day, twice daily treatment with 5 mg/kg AMPH in

spontaneously hypertensive rats, a model for ADHD.

The genes showing altered expression belonged to
several functional categories, including those involved
in transcription, angiogenesis, cell adhesion, apoptosis,
and neuronal development (Dela Pena et al., 2015).
Furthermore, changes in epigenetic markers such as
methylation status have been reported in several brain
regions, including the NAc, after 2 weeks of amphetamine exposure (Mychasiuk et al., 2013). It is likely that
these changes also have an effect on synaptic and/or
structural plasticity in ways that have yet to be fully
characterized.
12. Glutamate and Amphetamine/Methamphetamine
Reinforcement/Extinction/Reinstatement. Like cocaine,
AMPH and METH produce CPP (Thorn et al., 2012;
Martin et al., 2013; Han et al., 2014) and are reliably
self-administered (Pickens and Harris, 1968; Balster
and Schuster, 1973; Piazza et al., 1989; Kitamura et al.,
2006). Involvement of glutamate-mediated processes
in AMPH reinforcement and SA has been welldocumented. For instance, mGlu5 receptor antagonists
produce a dose-dependent decrease in METH SA without affecting food reinforcement, suggesting that mGlu5
receptors are involved in the reinforcing effects of
METH, but not natural rewards (Osborne and Olive,
2008). Similar effects have been reported with the
mGlu2/3 antagonist LY379268 (1R,4R,5S,6R)-4-amino2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid)
(Crawford et al., 2013; Kufahl et al., 2013). The mGlu5
receptor is also involved in extinction learning, because
administration of an mGlu5-positive allosteric modulator resulted in more rapid extinction of responding on
the active SA lever. However, this effect was not present
during reinstatement tests or a second extinction
session (Kufahl et al., 2012). Modulation of addictive
behavior was also observed in mGlu5-KO mice, which
showed decreased extinction of drug-seeking behavior
and increased cue-induced reinstatement (Chesworth
et al., 2013). Negative allosteric modulation of mGlu5
receptors was similarly found to attenuate both drugand cue-induced reinstatement of METH-seeking behavior, although it produced a similar effect on sucrose
and food seeking (Watterson et al., 2013).
Ionotropic glutamate receptors are also involved in
AMPH-induced addictive behavior (discussed in detail
in section II.A on cocaine; Fig. 6). NMDAR subunit
GluN2A-KO mice fail to display behavioral sensitization and activation of Ca2+-dependent intracellular
signaling pathways in the NAc in response to repeated
METH treatments (Miyazaki et al., 2013). In animals
trained to self-administer METH, striatal AMPAR
GluA2 subunit mRNA was increased 2 hours after
cessation of drug intake but decreased after 24 hours
compared with control animal (Currington et al., 2011).
METH-induced CPP was associated with increased
surface expression of GluA1 and GluA2 subunits in
the BLA (Yu et al., 2013). In the striatum, however,

Drug-Induced Neuroplasticity

a decrease in GluA1 and GluA2 mRNA and protein

levels as well as in those for GluN1 subunits and
increased AMPAR/NMDAR ratio has been reported in
response to repeated METH exposure (Jayanthi et al.,
2014). Furthermore, this treatment decreased enrichment of acetylated histone H4 on GluA1, GluA2, and
GluN1 promotors as well as a number of other epigenetic markers, whereas the expression of these AMPAR
and NMDAR subunits was blocked by the histone
deacetylase inhibitor, valproic acid, suggesting an
epigenetic mechanism, despite valproates limited specificity (Jayanthi et al., 2014). Changes in AMPAR
surface expression may also be mediated by striatalenriched tyrosine phosphatase isoform 61, which internalizes AMPARs, as one study demonstrated that the
decreases in striatal-enriched tyrosine phosphatase
isoform 61 increases in GluA2 surface expression and
behavioral sensitization after repeated METH treatments were blocked by an mGlu5 negative allosteric
modulator (Herrold et al., 2013). Treatment with ceftriaxone, which increased glutamate transporter
mRNA in the mPFC, blocked METH-induced reinstatement of CPP (Abulseoud et al., 2012).
An interesting question is whether observed plasticity phenomena are drug dependent or if they are
primarily associated with development of SA or sensitization. METH-induced glutamatergic neuroplasticity
appears to be at least partially dependent upon concurrent development of addictive behaviors, rather than
the drug itself. One study investigated the effect of
noncontingent METH administration versus METH SA
and found important differences in the glutamatergic
response to a subsequent METH challenge after drug
withdrawal. In noncontingently dosed rats the challenge decreased extracellular glutamate levels in the
NAc, whereas in previously self-administering rats, an
increase in glutamate levels was observed. This increase was also associated with a larger increase in DA
levels (Lominac et al., 2012). Another study found
reduced basal glutamate levels in both the NAc and
PFC, but increased glutamate levels after reinstatement in self-administering rats compared with yoked
saline controls (Parsegian and See, 2014).
How does plasticity differ between METH and cocaine
exposures? One study demonstrating the similarities
between glutamate involvement in METH and cocaine
SA directly compared the effect of a selective mGlu1
receptor antagonist on both METH- and cocaineinduced behavior in squirrel monkeys. It reported that
the antagonist produced a reduction in SA of both drugs
and attenuated the increase in responding for food
rewards produced by both drugs (Achat-Mendes et al.,
2012b). DA receptors play an important role in mediating synaptic plasticity (Wolf et al., 2003; Luscher and
Malenka, 2011), and because both METH and cocaine
produce increases in extracellular DA levels in vivo, it is
not surprising that they produce similar neuroplastic

909

effects that may be related to the development of drug

dependence. On the other hand, differences also exist,
and it has been reported that METH, unlike cocaine, did
not alter NAc or PFC cell surface expression of AMPARs
or NMDARs during withdrawal (Boudreau and Wolf,
2005; Nelson et al., 2009), indicative of important
differences between the two drugs. Cotreatment with
a spin-trapping agent prevented AMPH-induced
increases in glutamate efflux, suggestive of a ROSdependent signaling pathway (Wolf et al., 2000). ROS
signaling may be more important during amphetamine
exposure compared with cocaine because of the increased intracellular ROS after release of DA from
vesicles and cytoplasmic oxidation. Clearly, further
work is needed to outline the similarities and differences between AMPH/METH and cocaine neuroadaptation, as well as its behavioral implications.
13. Long-term Neuroadaptation/Neurotoxicity after
Exposure to High Doses of Psychostimulants. In research on psychostimulant neuroplasticity there has
been a focus on the long-term after-effects of psychostimulants such as METH and MDMA. These
amphetamine-type psychostimulants are sometimes
referred to as club drugs, because they are commonly
consumed recreationally at music festivals and dance
clubs. This pattern of consumption is not generally
associated with the development of addiction, but users
will sometimes redose the drug repeatedly during one
sitting (binge), which has led to concern about the
possible long-term effects of this pattern of consumption
on the brain in terms of long-term neuroadaptation and
cognitive function, such as deficits in memory and
attention.
a. Effects on brain structure. Ricaurte et al. (1982)
demonstrated that high doses of METH (3 injections of
50 mg/kg spaced over 8 hours) to rats caused destruction
of nerve terminals in the striatum as observed 4 days
after the treatments with a silver staining method,
considered the gold standard of neurotoxicity testing
(Switzer, 2000). Furthermore, they reported that similar
regiments also reduced levels of DA and 5-HT both in the
striatum and other brain regions such as the FC and
amygdala (Ricaurte et al., 1980, 1982). The observation
that high doses of METH produced neurotoxicity, visible
as swollen fibers and nerve terminals indicative of
chromatolysis and axonal damage, has also been found
by other investigators (Escalante and Ellinwood, 1970;
Lorez, 1981). Recently, evidence of toxicity, measured by
silver staining, was observed for METH at even lower
doses (3  5 mg/kg) (Ares-Santos et al., 2014). Similar
results were reported by Molliver et al. (1990) for MDMA
(20 mg/kg twice daily for 4 days), who found evidence of
structurally damaged axons that appeared as swollen
stumps in cortical regions after visualization with silver
staining. The damage coincided with loss of fine 5-HT
axons in cortical regions 2 weeks after treatment visualized by 5-HT immunocytochemistry.

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Korpi et al.

b. Effects on neurochemistry. Quantitative ligand

binding and neurochemical methods suggest alterations in monoamine systems after METH. Numerous
studies have reported decreases in striatal DA and 5-HT
levels after treatment with METH, with at least partial
recovery over time (Wagner et al., 1980; Seiden et al.,
1988; ODell et al., 1991; Cass, 1996; Callahan et al.,
1998; Cass and Manning, 1999). DAT and SERT levels,
as measured by ligand binding or uptake measurements, are decreased after METH (Hirata and Cadet,
1997; Brown et al., 2000; Ladenheim et al., 2000;
Schroder et al., 2003; Armstrong and Noguchi, 2004).
Finally, decreases in the levels of and function of the
synthesizing enzymes TH and tryptophan hydroxylase
(TPH) have been reported repeatedly as well, also with
recovery occurring as the survival interval increases
(Hotchkiss and Gibb, 1980; Bakhit et al., 1981; Haughey
et al., 1999; Schroder et al., 2003).
In rodents, numerous studies demonstrate that
METH can affect 5-HT and DA axons. For instance,
METH produces axons that appear swollen and varicose and display a decrease in 5-HT immunoreactive
boutons (Fukui et al., 1989). Similarly, both METH and
AMPH were reported to produce reduction in THpositive neurons in the striatum and FC, with AMPH
also producing swollen and enlarged axons (Kadota and
Kadota, 2004; Bowyer and Schmued, 2006). MDMA
appears to have an effect on 5-HT, but not on DA axons.
For instance, decreased 5-HT-positive neurons were
observed in the parietal cortex and forebrain regions
after treatment with high doses of MDMA, and similar
to METH, the remaining axons were ablated or thick
and varicose. However, no damage was observed to the
cell bodies in the raphe nucleus or to catecholaminergic
neurons and, furthermore, the loss of 5-HT axons
recovered to a large extent after 1 year (Ohearn et al.,
1988; Molliver et al., 1990; Scanzello et al., 1993).
The available evidence for MDMA suggests that high
doses affect only the 5-HT system in rats, having no longlasting effects on the DA system. In rats, decreased levels
of 5-HT and SERT binding in several brain regions
including the striatum, HC, and hypothalamus have been
reported, as well as decreased TPH activity. The alterations of these markers commonly recovers with time,
and no studies report any alterations in the catecholaminergic systems (Armstrong and Noguchi, 2004; Stone
et al., 1986; Battaglia et al., 1987, 1988; De Souza et al.,
1990; Sprague et al., 1994). In mice, conversely, even very
high doses of MDMA (60 mg/kg) do not affect serotonergic
markers such as brain 5-HT levels or TPH activity (Stone
et al., 1987) but instead decrease the DA levels, particularly in the striatum (Logan et al., 1988; OCallaghan and
Miller, 1994). Thus, there appears to be an important
species difference, with MDMA affecting the 5-HT system
in rats but the DA system in mice.
Studies in nonhuman primates generally support the
neurotoxicity or plasticity profile also observed in rats,

with METH decreasing 5-HT, DA, DAT, TH, and

VMAT-2 binding in various brain regions such as the
striatum and cortex (Woolverton et al., 1989; McCann
et al., 1998b) and MDMA affecting only the 5-HT system
as observed by decreased levels of 5-HT and SERT
binding as well as loss of 5-HT-positive axons in several
brain regions including cortical regions and the HC,
again with at least partial recovery occurring as the
survival interval increases (Insel et al., 1989; De Souza
et al., 1990; Hatzidimitriou et al., 1999).
c. Effects on behavior. In addition to the neurochemical after-effects of high doses of METH and AMPH,
research has also focused on the potential consequences
on behavior, primarily by means of animal models of
cognition, anxiety, and depression and including memory tests such as the novel object recognition test and
the Morris water maze, tests of anxiety-like behavior in
emergence tests, elevated plus maze tests, and social
interaction tests as well as the forced swim test, said to
measure aspects of depression (McGregor et al., 2003b;
Clemens et al., 2004, 2007 Clemens et al., 2004). Overall, however, the results supporting long-term effects of
amphetamines on these behavioral tests are much less
consistent than the data from neurochemical studies,
often showing contradictory effects.
METH was shown to decrease recognition memory in
the novel object recognition test for up to several weeks
after drug treatments (Schroder et al., 2003; Marshall
et al., 2007; Herring et al., 2008). Also decreases in
spatial memory have been observed using tests such as
the radial arm maze and Morris water maze (Nagai
et al., 2007; Camarasa et al., 2010). However, other
studies report no effect on memory using the novel
object recognition test (Clemens et al., 2007), whereas
inconsistent results are obtained for anxiety-related
behavior depending on the type of test used, and no
effect was found on the forced swim test (Clemens et al.,
2004, 2007).
With MDMA, the evidence of persistent long-lasting
effects on rodent behavioral tests is also difficult to
interpret. Decreased recognition memory performance
(Mechan et al., 2002; Piper and Meyer, 2004) and
decreased performance in a delayed nonmatching to
place test (Marston et al., 1999) have been reported.
Evidence of depressive behavior measured as increased
immobility in the forced swim test and evidence of
anxiety-related behavior measured using several tests,
such as the social interaction and emergence test and
the elevated plus maze, have also been described
(McGregor et al., 2003a,b). On the other hand, decreases
in anxiety-like behavior after MDMA have been observed using these same tests (Mechan et al., 2002;
Piper and Meyer, 2004). Also memory deficits after
MDMA are not always observed. For instance, MDMA
has been reported not to affect object recognition
memory (McGregor et al., 2003a). Other studies also
found no evidence of impairment in animals tested on

Drug-Induced Neuroplasticity

a wide range of behavioral tests, including the radial

arm maze and the Morris water maze, despite the fact
that large decreases in cortical 5-HT levels were present
(Seiden et al., 1993; Marston et al., 1999). These results
indicate that the relationship between observed
monoamine system deficits and functional outcome
in terms of behavior and cognitive function is not
straightforward.
A number of limitations must be kept in mind when
interpreting the results from preclinical rodent studies.
Foremost, the use of allometric scaling to adjust for
differences in basal metabolic rate between humans and
rodents has led to rodents commonly being administered
relatively high drug doses, often in the 1020 mg/kg
range or higher. However, the use of allometric scaling
has been criticized for drugs such as MDMA, which
display nonlinear kinetics and are extensively metabolized (Baumann et al., 2007). When employing effects
scalingbased on selecting doses required to achieve
similar amounts of 5-HT release, prolactin secretion,
reinforcement, or drug discriminationthe required
doses are in the 13 mg/kg range, closely corresponding
to the doses used recreationally by humans. More importantly, when administered at these doses (,5 mg/kg)
there is no evidence of long-lasting monoamine depletions (OShea et al., 1998; Baumann et al., 2007).
Furthermore, high doses of the drugs are often given
to animals without any preconditioning to lower doses,
something that would more correctly model human use
and has shown to be protective in animal models (see
below). Finally, a majority of studies report on the effect
on measures such as levels of monoamines and their
transporters and synthesizing enzymes. One can contend whether this reflects actual toxicity or rather longterm adaptation, particularly as these changes are
not always associated with deficits in behavioral tests
and because higher doses are commonly needed to
produce toxicity as measured by methods such as Fluoro
Jade B staining and gliosis marker levels (Baumann
et al., 2007)
14. Limited Evidence for Long-term Effects of
Substituted Cathinones in Rodent Models. Recent
studies on the effects of the substituted cathinones 4MMC and MDMC show much more limited long-term
effects of these drugs on the monoamine systems
compared with METH and MDMA. When 4-MMC is
administered at three injections of up to 10 mg/kg there
was no long-lasting decrease in striatal or cortical
monoamine levels in rats (Baumann et al., 2012).
Interestingly, also intense, high-dose binge treatments
of four injections of up to 40 mg/kg spaced 2 hours apart
failed to produce any decreases in striatal DA levels
(Angoa-Perez et al., 2012). The lack of effect of 4-MMC
on the monoamine system is corroborated by two other
studies employing various dosing regimens such as
30 mg/kg once daily for 10 days (Motbey et al., 2013)
or twice daily for 4 days (den Hollander et al., 2013),

911

which both failed to observe any decreases in monoamine levels in the striatum, cortex, and HC at
a survival interval between 14 and 43 days after the
final 4-MMC treatment. The only studies so far that did
observe an effect of 4-MMC on markers of the monoamine system, such as DAT, SERT, TPH, and TH levels
and functions, were the studies in which the drugs were
administered at elevated (.26C) ambient temperatures (Hadlock et al., 2011; Martinez-Clemente et al.,
2014). High ambient temperatures produce a general
increase in amphetamine neurotoxicity (see below), and
these studies indicate that this also holds true for
cathinones. Furthermore, there is evidence that 4MMC can increase the loss of striatal DA induced by
METH when the two drugs are coadministered (AngoaPerez et al., 2013b), but does not exacerbate the loss of 5HT after METH or MDMA (Angoa-Perez et al., 2013a).
MDMC has so far been less studied, but the available
evidence suggests that it does not have an effect on
monoamine levels at doses of up to three times 10 mg/kg
(Baumann et al., 2012), whereas high doses (30 mg/kg
twice daily for 4 days) produce decreases in 5-HT levels
in the cortex, striatum, and HC at a 2-week survival
interval (den Hollander et al., 2013).
Regarding the effects of these drugs on behavioral
tests of cognition, the data are less clear. Although
a decrease in recognition performance in the novel
object recognition test was observed 1 month after
treatment with 4-MMC (Motbey et al., 2012), as well
as a decrease in working memory measured using the
T-maze spontaneous alternation test, there were no
effects on spatial memory in the Morris water maze test.
Furthermore, both 4-MMC and MDMC have no effect on
anxiety-like behavior measured using the emergence
test or elevated plus maze or on depressive behavior in
the forced swim test and actually appear to improve
aspects of spatial reversal learning (den Hollander
et al., 2013).
15. Mechanisms Involved in Long-term Adaptation
and Neurotoxicity. The four primary mechanisms responsible for producing neurotoxicity after exposure to
amphetamines are oxidative stress, mitochondrial dysfunction, excitotoxicity, and hyperthermia (Fig. 8).
Additionally, a number of other factors including inflammation, microglial activation, blood-brain barrier
disruption, and altered neurogenesis play a role,
whereas neuroplasticity associated with low-dose
AMPH preconditioning may provide protective effects.
A summary of the primary mechanisms is provided
here, whereas more in-depth information can be found
in relevant reviews (Yamamoto et al., 2010; Carvalho
et al., 2012; Goncalves et al., 2014; Halpin et al., 2014)
a. Oxidative stress: DA oxidation and drug metabolites as sources of reactive species. Support for the
involvement of oxidative stress as a causal mechanism
in amphetamine toxicity comes from a number of
studies demonstrating attenuation of METH- and

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Korpi et al.

MDMA-induced monoamine loss after coadministration of spin-trapping agents or antioxidants such as

N-acetylcysteine, ascorbic acid, vitamin E, and selenium
(Wagner et al., 1985; De Vito and Wagner, 1989; Colado
and Green, 1995; Fukami et al., 2004; Barayuga et al.,
2013). Accordingly, depletion of glutathinone, inhibition
of superoxide dismutase, and selenium-deficient diets
increase toxicity (De Vito and Wagner, 1989; Sanchez
et al., 2003; Chandramani Shivalingappa et al., 2012).
One of the primary sources of oxidative stress after
amphetamines is the large increase in cytoplasmic and
extracellular DA levels and the subsequent metabolism
of DA into toxic metabolites (Yamamoto and Raudensky,
2008). DA can be both enzymatically and nonenzymatically metabolized, with both routes resulting in
production of reactive products. When MAO metabolizes large amounts of DA, the resulting byproduct
hydrogen peroxide may rise to levels exceeding the
detoxification capacity of the glutathione system. Subsequently, the hydrogen peroxide can react with Fe2+,
resulting in the production of the highly reactive
hydroxyl radical. Moreover, both DA and its metabolite
3,4-dihydroxyphenylacetaldehyde can undergo autooxidation to form superoxide and reactive semiquinones
(LaVoie and Hastings, 1999; Sulzer and Zecca, 2000;
Anderson et al., 2011; Munoz et al., 2012). Accordingly,
reducing intracellular DA through blockade of DAT or
inhibition of DA synthesis reduces the METH toxicity

(Schmidt et al., 1985; Marek et al., 1990; Yamamoto and

Zhu, 1998).
Other potential sources of reactive species are amphetamine molecules themselves. Particularly MDMA
has received attention in this respect, because certain
catechol-like hepatic metabolites of MDMA are thought
to be capable of auto-oxidizing and producing reactive
quinones capable of forming thioether conjugates with
sulfur-containing compounds such as glutathione and
N-acetylcysteine. These thioether compounds retain the
ability to redox cycle and are toxic to 5-HT neurons. In
fact, they are more toxic than MDMA itself (Monks
et al., 2004; Ferreira et al., 2013) and have also been
detected in vivo after MDMA exposure (de la Torre and
Farre, 2004; Perfetti et al., 2009). Nonetheless, DA
remains an important factor also in MDMA-induced
5-HT toxicity (Stone et al., 1988; Schmidt et al., 1990;
Shankaran et al., 1999; Falk et al., 2002; Breier et al.,
2006).
b. Mitochondrial dysfunction: ATP deficit, superoxide
leakage, and apoptosis. METH and MDMA are known
to decrease the levels and activity of mitochondrial
complexes I, II, and IV in the striatum (Burrows et al.,
2000; Brown et al., 2005; Klongpanichapak et al., 2006;
Puerta et al., 2010). MDMA was also shown to cause
deletions in mitochondrial DNA coding for subunits of
complexes I and IV (Alves et al., 2007). More recently
it was shown that even relatively low doses of both

Fig. 8. Summary of various mechanisms and factors involved in cellular toxicity by amphetamine-type stimulants.

Drug-Induced Neuroplasticity

AMPH and METH (2 mg/kg or less) decrease complex I,

II, or IV activity in various brain regions, including the
striatum, FC, and amygdala, obtained from animals
killed while still under the influence of the drugs (Feier
et al., 2012). Inhibition of the mitochondrial electron
transport chain (ETC) by amphetamines can result in
reduced ATP levels but also causes excessive leakage of
superoxide, increasing oxidative stress and possibly
triggering apoptosis.
METH decreases ATP levels in the striatum and
cerebral cortex while increasing AMP levels (Shiba
et al., 2011). The importance of decreased ATP levels
in amphetamine toxicity is demonstrated by an experiment where neural glucose uptake was prevented by
administration of 2-deoxyglucose, a manipulation that
enhanced both the decrease in ATP levels observed
directly after METH treatment as well as the loss of
striatal DA 1 week later (Chan et al., 1994). Similarly,
inhibition of metabolism by directly interfering with the
ETC also increases toxicity because the potent complex
II inhibitor malonate exacerbated both METH and
MDMA toxicity (Burrows et al., 2000; Darvesh et al.,
2005), whereas application of the energy substrates
decylubiquinone or nicotinamide 6 hours after METH
treatment reduced toxicity (Stephans et al., 1998).
ETC inhibition can also exacerbate amphetamine
toxicity by increasing oxidative stress. During normal
oxidative phosphorylation, approximately 14% of mitochondrial oxygen will be reduced to superoxide.
However, during inhibition of mitochondrial complexes,
the electron leak and superoxide production will increase dramatically. The resulting increase in oxidative
stress adds to the stress already occurring from DA
oxidation and represents a key factor in mediating
amphetamine toxicity (Brown and Yamamoto, 2003;
Adam-Vizi, 2005).
The mitochondrial-dependent apoptotic pathway has
also been suggested to play a role in amphetamine
toxicity (Cadet et al., 2005). METH increases the
expression of proapoptotic genes BAD, BAX, and BID,
while decreasing the expression of antiapoptotic genes
Bcl-2 and Bcl-XL (Jayanthi et al., 2001; Krasnova et al.,
2005; Beauvais et al., 2011). Indeed, METH has been
shown to trigger the release of apoptosis inducing
factor, cytochrome c, and smac/DIABLO from mitochondria, eventually leading to the recruitment of caspases
and the initiation of apoptotic cell death (Jayanthi et al.,
2004). As expected, both overexpression of Bcl-2 and
inhibition of caspases protect against METH toxicity
(Cadet et al., 1997, 2003; Uemura et al., 2003). However,
the apoptotic effect has primarily been observed after
extremely high doses of METH or in vitro, and its
relevance for human users remains unclear.
c. Excitotoxicity: glutamate receptor involvement and
intracellular excitotoxic processes. Studies employing
in vivo microdialysis have shown that METH increases
glutamate release in the striatum (Mark et al., 2004;

913

Nash and Yamamoto, 1992; Stephans and Yamamoto,

1994) and that blockade of glutamate receptors attenuates METH-induced depletion of striatal DA and other
markers of toxicity (Farfel et al., 1992; Bowyer, 1995;
Battaglia et al., 2002; Shah et al., 2012), indicating
that glutamate receptor-mediated processes are involved in METH toxicity. Conversely, MDMA appears
to reduce glutamate release in certain brain regions,
and the importance of excitotoxicity in mediating
MDMA-induced 5-HT toxicity is still unclear (Capela
et al., 2009).
One event associated with increased Ca2+ levels that
is observed after amphetamine exposure is proteolysis
of the cytoskeletal proteins, such as calpain-mediated
cleavage of spectrin (Lee et al., 1991). Spectrin proteolysis has been observed in the rat striatum after
METH treatments, whereas METH- and MDMAinduced increases in calpain activation and spectrin
proteolysis were blocked by the calpain inhibitor calpastatin in vitro (Staszewski and Yamamoto, 2006;
Warren et al., 2007; Suwanjang et al., 2012).
Excitotoxic processes can also lead to increased production of reactive species. Nitric oxide synthase is
elevated during METH exposure, and NO can readily
react with superoxide to produce peroxynitrite, a highly
reactive anion that produces toxicity through nitrosylation. Direct evidence for its involvement in METH
toxicity comes from data showing that METH-induced
depletion of DA is accompanied by increased levels of
striatal nitrate and nitrotyrosine (Anderson and Itzhak,
2006; Pacher et al., 2007; Wang et al., 2008b). Furthermore, blockade of nitric oxide synthase provides full
protection against METH-induced loss of DA (Itzhak
and Ali, 1996), whereas coadministration of a peroxynitrite decomposition catalyst partially prevents toxicity
(Imam et al., 1999). Specific targets have also been
identified as METH-induced nitrosylation, coupled with
loss of function, and have been observed on the VMAT-2
protein (Eyerman and Yamamoto, 2007). In addition to
nitric oxide synthase, other enzymes may also be
involved. Activation of xanthine oxidase can result in
increased superoxide production, whereas cleavage of
membrane phospholipids and release of arachidonic
acid by phospholipase A2 may also result in production
of superoxide after lipoxygenase- and cyclooxygenasemediated metabolism of arachidonic acid (Battelli et al.,
1995; Yamamoto and Raudensky, 2008).
d. Hyperthermia: a catalyst of other toxic processes.
Hyperthermia plays a well-established and important
role in mediating amphetamine toxicity. Both METH and
MDMA produce hyperthermia, and preventing the hyperthermia provides protection against subsequent neurotoxicity. Furthermore, lower ambient temperatures
attenuate, whereas higher ambient temperatures exacerbate, both METH and MDMA toxicity (Ali et al., 1994;
Bowyer et al., 1994; Broening et al., 1995; Malberg and
Seiden, 1998; Goni-Allo et al., 2008). Hypophysectomy,

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Korpi et al.

thyroparathyroidectomy, as well as treatment with high

doses of haloperidol or diazepam that reduce body
temperature during amphetamine treatments, also reduce the observed toxicity (Bowyer et al., 1994; Sprague
et al., 2003). A large number of neurotransmitter systems
appears to be involved in producing the hyperthermic
effect, because blockade of receptors, including the
NMDAR; D1R, D2R, and D3R; a1-adrenoreceptors;
5-HT2 receptors; as well as the s and OX1 receptors,
all prevent or reduce METH-induced hyperthermia
while protecting against METH toxicity (Sonsalla
et al., 1991; Farfel et al., 1992; Doyle and Yamamoto,
2010; Seminerio et al., 2011, 2012; Rusyniak et al.,
2012; Ares-Santos et al., 2012; Kikuchi-Utsumi et al.,
2013; Robson et al., 2013a; Sabol et al., 2013; Baladi
et al., 2014).
The effect of body temperature on amphetamine
toxicity appears to depend on a specific interaction,
because hyperthermia on its own does not produce
METH-characteristic toxicity (Bowyer, 1995). The effect
of temperature is most likely due to a general catalytic
effect on the enzymatic and nonenzymatic reactions,
such as those resulting in production of reactive species.
For instance, it has been shown that hypothermia
prevents METH-induced oxidative stress (Fleckenstein
et al., 1997c; Yamamoto et al., 2010), whereas hyperthermia significantly increases oxidative stress and
other measures of toxicity (Silva et al., 2014).
Interestingly, the cathinone 4-MMC produces transient hypothermia rather than hyperthermia in rats
(Shortall et al., 2013), and its neurotoxicity is enhanced
in mice at elevated ambient temperature (26 C) when it
causes hyperthermia (Miller et al., 2013). By using
telemetric body core temperature monitoring in mice, it
was found that high doses of 4-MMC produced complex
changes, first inducing hypothermia that was followed
by hyperthermia (Angoa-Perez et al., 2012).
e. Other factors: inflammation, blood-brain barrier
disruption, protective preconditioning. Recently, there
has been more focus on additional factors that may
mediate amphetamine neurotoxicity. METH- and
MDMA-induced activation of microglia and subsequent
increases in proinflammatory cytokines contribute to
toxicity. In contrast, 4-MMC has failed to induce striatal
microglial activation and astrogliosis even at high doses
in mice, although METH was active in the same
conditions (Angoa-Perez et al., 2012). Similarly,
amphetamines are reported to produce defects in the
ubiquitin proteasomal system and blood-brain barrier
integrity, whereas stress and human immunodeficiency
virus infection also represent modulatory factors
(Yamamoto et al., 2010). Alterations in neurogenesis
from the subventricular zone stem/progenitor cells and
the dentate gyrus have also been reported (Goncalves
et al., 2014), and toxic products such as ammonia,
resulting from METH-induced damage to peripheral
organs may play a further role in mediating neurotoxicity

(Xie and Miller, 2009; Seminerio et al., 2013; Halpin et al.,

2014 ).
There are also factors that mediate neuroprotection,
such as preconditioning with low doses of amphetamines before a toxic challenge. Preconditioning with
escalating doses of METH (0.52.5 mg/kg) for up to 2
weeks before a subsequent toxic METH challenge
provides full protection against METH-induced DA
toxicity (Graham et al., 2008; Cadet et al., 2009; Hodges
et al., 2011). Possible mechanisms have been investigated in an in vitro study that found that low concentrations of METH produced changes in the pERK1/2
level, by decreasing it in basal conditions and increasing
it in response to the toxic 6-hydroxydopamine challenge
(El Ayadi and Zigmond, 2011). METH also upregulated
levels of the antiapoptotic protein Bcl-2. Also voluntary
running wheel endurance-type exercise in mice has
been shown to be protective against METH toxicity,
an effect that appears to be mediated by antioxidant
adaptations in brain microvasculature and tightjunction proteins at the blood-brain barrier (Toborek
et al., 2013). Meanwhile, for MDMA it was shown that
pretreatment with a low doses (3 mg/kg) protected
against toxicity of a subsequent toxic dose of MDMA
(12.5 mg/kg) administered 1 week later. The pretreatment was associated with increased levels of the inflammatory cytokine IL-1b after 6 hours, while slowly
producing a significant increase in the interleukin
receptor antagonist IL-1ra reaching a peak 4 days after
the preconditioning (Cohen et al., 2013). The neuroplasticity that occurs in response to changes in cellular
inflammatory and oxidative stress processes may play
an important role in modulating potential neurotoxicity
in humans, because such preconditioning may happen
naturally during dose escalation that occurs in human
users.
16. Evidence of Long-term Plasticity and Cognitive
Effects after Stimulant Use in Humans.
a. Cognitive behaviors. Deficits in abstinent METH
users compared with control subjects have been observed on tests such as immediate and delayed recall
and digit span tests and measuring performance on
memory-related domains, such as verbal memory, longterm declarative memory, and working memory. Deficits are also observed on tests such as the Wisconsin
card sorting test, Stroop test, and trail-making test,
indicating deficits in the cognitive domains of executive
function and attention (Simon et al., 2000; Kalechstein
et al., 2003; Han et al., 2008; Rendell et al., 2009).
Furthermore, METH users appear to experience higher
levels of anxiety and depression than nonusers (Zweben
et al., 2004; Vik, 2007).
Similar to METH, abstinent MDMA users also show
deficits in certain cognitive domains. The most common
observations include deficits in short-term and longterm memory, verbal reasoning, attention, and executive functions as well as decreased performance in tests

Drug-Induced Neuroplasticity

reflecting aspects of general intelligence (Parrott et al.,

1998; McCann et al., 1999; Gouzoulis-Mayfrank et al.,
2000; Heffernan et al., 2001; von Geusau et al., 2004).
Other studies of abstinent MDMA users have also
reported higher ratings of depression and anxiety in
addition to decreases in memory performance (McCardle
et al., 2004; Thomasius et al., 2006). However, many
studies do not properly match MDMA users and
controls in terms of education, intelligence quotient,
and other variables. When subjects are properly
matched, no consistent detrimental effects of MDMA
are observed (Halpern et al., 2011).
b. Brain imaging of receptors, transporters and
activity/metabolism. PET scans have been used to
assess monoamine-related ligand binding in human
amphetamine users. Similar to what is seen in animals,
decreased DAT and VMAT2 binding has been observed
in the striatum and FC of abstinent METH users, who
also performed lower than controls on measures of
cognitive function, including memory. However, correlations between DAT binding and the time of abstinence
or between DAT binding and measures of cognitive
function were not always observed (McCann et al.,
1998a, 2008; Sekine et al., 2001; Johanson et al., 2006).
PET studies measuring cerebral metabolism have also
reported differences between abstinent METH users and
nonusers. For instance, it was reported that METH users
showed decreased metabolism in the parietal cortex and
thalamus (Volkow et al., 2001), whereas hypometabolism
is observed in the FC of METH users, who also made
more errors of preservation on the Wisconsin card sorting
test than control subjects (Kim et al., 2005, 2009).
Decreased performance of METH users on a vigilance
task and increases in anxiety and depression-like symptoms were associated with lower metabolism in the
cingulate and insula but higher metabolism in the FC.
Moreover, in METH users, task performance was negatively correlated with metabolism in the cingulate and
insula, whereas a positive correlation was observed in
controls (London et al., 2004, 2005).
Abstinent MDMA users show decreases in SERT
binding in several brain regions, including cortical
regions, thalamus, hypothalamus, and striatum, and
the extent to which the binding is decreased is correlated with the amount of previous MDMA use. Additionally, abstinent MDMA users perform worse on tests
of memory function, and their performance on these
tests is correlated with insular and hippocampal SERT
binding (McCann et al., 1998a, 2008; Kish et al., 2010).
However, a previous SPECT study found decreased
SERT binding only in abstinent female, but not male,
subjects. Furthermore, the decreased binding appeared
to recover with protracted abstinence, reaching a level
higher than control subjects (Reneman et al., 2001a).
Decreased metabolism has also been reported in MDMA
users in the cingulate, HC, amygdala, and striatum;
however, no correlation was found between metabolism

915

and the amount of MDMA consumed (Obrocki et al.,

1999; Buchert et al., 2001). Brain 5-HT2A receptor
binding in MDMA users appears to be decreased in all
cortical regions, whereas abstinent users show increased 5-HT2A receptor binding, but only in the
occipital cortex (Reneman et al., 2002). Furthermore,
the abstinent MDMA users scored lower on a test of
verbal memory, and memory performance was positively correlated to the amount of 5-HT2A receptor
binding (Reneman et al., 2000). However, the relationship between memory function and 5-HT2A receptor
binding is hard to interpret, because the abstinent users
had higher levels of 5-HT2A binding than controls but an
overall lower memory performance.
c. Magnetic resonance imaging studies. Both structural and functional MRI studies have reported differences between METH users and nonusers. It has been
reported that abstinent METH users have lower gray
matter density in the FC as well as decreased Wisconsin
card sorting test task performance compared with drugfree control subjects (Kim et al., 2006). Decreased
cingulate and hippocampal volumes that correlated
with performance on a verbal memory test (Thompson
et al., 2004) and correlations between increased METH
exposure and reductions in orbital and medial PFC
volumes have also been noted (Daumann et al., 2011).
Interestingly, striatal volume is reportedly increased in
abstinent METH users in a study that, however, did not
find any evidence of decreased cognitive performance
(Chang et al., 2005). Another study also found increased
putamen volume in METH users that correlated negatively with performance on the go/no-go test for impulsivity (Jan et al., 2012). Decreased volumes of certain
cortical regions and the HC have also been reported in
MDMA users (Cowan et al., 2003; den Hollander et al.,
2012).
Functional MRI studies also report differences between amphetamine users and nonusers. Two studies
reported that METH users showed increased impulsivity as measured by a delay-discounting test and showed
decreased activity in the cingulate and dorsolateral
PFC (Monterosso et al., 2007; Hoffman et al., 2008).
Decreased activation was also observed in the frontal
and insular cortices of METH users in response to
a Stroop task, although task performance was not
consistently different from control subjects (Salo et al.,
2009; Nestor et al., 2011).
In fMRI studies of MDMA users, a weaker BOLD
signal during working memory task performance was
noted in the frontal and temporal cortex in heavy
compared with light users, but when comparing users
to nonusers there was no clear effect on BOLD signal
and, furthermore, task performance was also similar
between MDMA users and controls (Daumann et al.,
2003). Increases in BOLD signal in the frontal gyrus in
response to a memory task on which MDMA users also
were not impaired have been reported as well (Moeller

916

Korpi et al.

et al., 2004). Differences in hippocampal BOLD signal in

response to episodic or associative memory tasks
revealed decreases in MDMA users versus controls
and in continuing versus abstinent MDMA users;
however, here also there were no differences observed
on the actual task performance (Daumann et al., 2005;
Becker et al., 2013). It is possible that differing cognitive
strategies between users and nonusers may account for
the observed variability in BOLD signal intensity
(Honey et al., 2000).
d. Magnetic resonance spectroscopy and analysis of
postmortem tissue. In addition to alterations in structural and functional MRI studies, alterations have also
been reported in cerebral blood flow and white matter
integrity using perfusion and fractional anisotropy MRI
techniques (Iyo et al., 1997; Chang et al., 2002; Alicata
et al., 2009). Furthermore, magnetic resonance spectroscopy has been employed to detect changes in chemical
markers, such as N-acetylaspartate, choline, creatine,
and phosphocreatine, putatively reflecting abnormalities
in neuronal cell membrane integrity or metabolism
(Panenka et al., 2013). Decreases in phosphocreatine
and correlations between N-acetylaspartate/creatine ratio and verbal memory performance have been reported
in METH and MDMA users, respectively (Reneman et al.,
2001b; Sung et al., 2013).
Analyses have also been made of postmortem brain
material, and a decrease in striatal DA, DAT, and TH
levels has been reported (Wilson et al., 1996). Decreases
in D1R-mediated stimulation of adenylyl cyclase (AC) in
response to DA, suggestive of alterations in the level
and function of DA-related proteins, have also been
reported (Tong et al., 2003). However, because brains in
these studies are primarily sourced from individuals
who overdosed on METH, their relevance for normal
recreational users must be questioned.
e. Prospective and experimental studies.
Neurocognitive studies in humans have produced vastly
divergent results, with certain studies reporting decreased performance on various measures of cognitive
performance, whereas others report no difference. Furthermore, specific deficits are not often replicated
between studies. Neuroimaging studies also suffer from
large result variability, with various differences in taskrelated signal intensities, which often occur without any
overt effect on task performance. Another major issue
confounding the interpretation is that causality cannot
be determined from cross-sectional studies, and it is
likely that pre-existing differences between MDMA
users and control subjects account of a large part of
the observed differences.
Prospective studies have been performed to address
some of these issues. In a Dutch study, subjects who
were considered to be at high risk of commencing
MDMA use were recruited for an in-depth set of neuroimaging experiments, both at baseline before any
MDMA and at a follow up within 3 years after the

baseline scans. The individuals who started using

MDMA displayed a slight decrease in regional relative
cerebral blood flow in the globus pallidus and putamen
as well as decreased fractional anisotropy in the
thalamus and frontoparietal white matter. However,
no effect was found on N-acetylaspartate/creatine ratio,
and, importantly, no difference was found on the most
important measure, namely SERT binding between
new MDMA users and those who remained MDMA
naive. A dose-response relationship between cumulative MDMA use and SERT binding was also not present,
suggesting that low-dose MDMA use (mean of six
tablets) has no effect on SERT-binding in novel MDMA
users (de Win et al., 2008).
The same population was also subjected to a wide
array of neurocognitive tests. Subjects who commenced
MDMA use scored significantly lower on immediate and
delayed verbal recall compared with MDMA-naive
subjects; however, no effects were observed on any other
neurocognitive tests, and all scores were within the
normal ranges. Importantly, the verbal memory scores
of MDMA users did not decrease between the baseline
and follow up, and the difference between users and
nonusers was actually due to an increase in performance of the nonusers during the follow up, suggesting
that low-dose MDMA use has no effect on measures of
neurocognitive function, including memory (Schilt
et al., 2007; Krebs and Johansen, 2008).
A second prospective study focused specifically on
users who had a higher MDMA consumption, excluding
subjects who had used less than 10 tablets and thus
comparing heavier users (mean of 34 tablets) to individuals having consumed cannabis only. Like in the
Dutch study (de Win et al., 2008), no effects were found
on verbal memory, and significant differences between
groups being reported only for immediate and delayed
visual memory. Here, the difference was due to a decreased performance in the MDMA users (Wagner et al.,
2013).
Although prospective studies are more informative
than cross-sectional studies, there are still a number of
confounding factors that only experimental studies can
address. Although a number of studies have administered METH or MDMA experimentally to humans (Mas
et al., 1999; Harris et al., 2002; Hart et al., 2012;
Carhart-Harris et al., 2014), long-term cognitive outcomes have usually not been reported. One study that
did reported no effects on cognitive function measured
at 1 year or longer after the drug treatments (Mithoefer
et al., 2013). In summary, although a number of crosssectional studies report cognitive and neurologic deficits
or alterations as a result of the use of amphetamines,
these studies often suffer from methodological limitations that could lead to overestimation of the actual
drug effect. Most results are not replicated in prospective or experimental studies and, furthermore,
although amphetamine users sometimes score lower

Drug-Induced Neuroplasticity

than control subjects, they still score well within the

normal range (Hart et al., 2012), suggesting that any
existing drug effect is very limited and does not produce
any clinically significant impairment.
17. Conclusions. Amphetamines are a class of drugs
that exert powerful stimulatory effects on brain function
by mechanisms that include the inhibition of monoamine
reuptake and enhancement of monoamine release. They
are used medically to treat disorders such as ADHD, but
nonmedical recreational use of amphetamines is also
widespread, because amphetamines are the second most
commonly used illicit drug after cannabis. A large
number of animal studies indicate that amphetamines,
in addition to being addictive, are neurotoxic and even
lethal at high doses. It is still unclear whether similar
neurotoxicity occurs in human recreational users. Some
studies suggest that amphetamine users may display
certain abnormalities in the monoamine systems reminiscent of neurotoxicity observed in animals after highdose treatments. However, because most studies are
cross-sectional, no clear conclusions can be drawn with
regards to causality. Furthermore, amphetamine users
do not show any clear evidence of persistent functional
deficits and consistently score within normal ranges on
neuropsychological tests of memory function.
C. Nicotine
Smoking has been estimated to cause smokers to lose
one decade of their lives compared with never-smokers
(Jha et al., 2013). Early smoking cessation (,40 years of
age) seems to give back most of those years, indicating
some reversibility of smoking-related damage in the
body.
Nicotine is the principal neuroactive alkaloid responsible for tobacco addiction (Jaffe and Kanzler, 1979;
Stolerman and Jarvis, 1995; Pontieri et al., 1996; Pich
et al., 1997). Despite widespread prevalence of tobacco
smoking, it was not until the mid-1990s that there was
a scientific consensus that nicotine is addictive in
a similar manner to other drugs of abuse such as cocaine
(Stolerman and Jarvis, 1995; Pontieri et al., 1996; Pich
et al., 1997). Recent studies have shown that nonnicotine components in tobacco are also reinforcing or
influence nicotine SA. Anabasine dose dependently
increased nicotine SA at 0.02 mg/kg s.c. in rats, whereas
both anabasine and anatabine reduced nicotine SA at
2 mg/kg s.c. (Hall et al., 2014). Another non-nicotine
tobacco component, norharmane, was behaviorally
reinforcing on its own, and these reinforcing effects
were additive with those of nicotine (Arnold et al., 2014).
Norharmane is a MAO inhibitor. It has been suggested
that the inhibition of MAOs contributes to the rewarding effects of nicotine (reviewed in Kapelewski et al.,
2011).
Smoking is well known to be associated with many
adverse effects, including increased risk of cancers and
cardiovascular disease. Although the abuse potential

917

and harmful effects of nicotine were recognized, there

continued to be interest in the potential beneficial acute
effects of nicotine for cognitive enhancement (Everitt,
1997; Robbins et al., 1997; Changeux et al., 1998; Levin,
2013) and neuroprotection (Buckingham et al., 2009;
Hernandez and Dineley, 2012; Kawamata et al., 2012).
Others pointed to cognitive impairment in heavy smokers during abstinence as evidence of adverse effects on
neural plasticity associated with learning and memory
(Abrous et al., 2002). The diversity of nicotinic acetylcholine receptor subtypes contributes to the diverse
functional effects of nicotine.
1. Nicotinic Acetylcholine Receptors. Nicotinic acetylcholine receptors (nAChRs) belong to the "Cys-loop"
superfamily of multisubunit transmembrane ionotropic
neurotransmitter receptors (Albuquerque et al., 2009).
High-resolution structural studies have shown that
nAChRs are assembled from five subunits, which form
to create a central pore (Unwin, 2005; Baenziger and
Corringer, 2011). Sixteen different subunits have been
identified in mammals (Millar and Gotti, 2009). Of the
mammalian nAChR subunits, only a7 and a9 can form
homopentamers and only a7 forms endogenous homopentameric receptors (Vetter et al., 2007; Millar and
Gotti, 2009). The other a subunits usually form heteropentamers containing two a subunits and three b
subunits. Receptor subtypes are named according to
their subunit composition, with an asterisk used to
indicate cases where one or more additional subunit
types may also be present (Lukas et al., 1999; Millar
et al., 2014). nAChRs composed of different subunits are
differentially distributed throughout the brain. a4b2,
a4a5b2, a3b4*, a6b2b3*, and a7 are expressed in the
VTA and SN; a4b2 and a7 in the hypothalamus; a4b2,
a4a5b2, a6b2b3, and a6a4b2b3 in the striatum; a4b2,
a4a5b2, a3b4, and a7 in the HC; and a4b2, a4a5b2, and
a7 are expressed in the cerebral cortex (Gotti et al.,
2006, 2007). Nicotine is an agonist at all nAChRs except
for a9/10 nAChRs, expressed by vestibular and cochlear
mechanosensory hair cells (Elgoyhen et al., 2001; Scholl
et al., 2014) and a subset of dorsal root ganglion sensory
cells (Papadopolou et al., 2004), at which nicotine is an
antagonist (Elgoyhen et al., 2001; Millar et al., 2014).
nAChRs are widely expressed in the midbrain DAergic
neurons projecting to the dorsal striatum, ventral
striatum and NAc, and PFC. A remarkable diversity of
b2* nAChR subtypes modulates DA release in these
projections (Grady et al., 2007; Gotti et al., 2009;
Livingstone and Wonnacott, 2009). These projections,
in particular those to the NAc and ventral striatum, are
likely involved in reward pathways and the reinforcing
properties of nicotine contributing to addiction. Nicotine increases firing of midbrain DA neurons (Grenhoff
et al., 1986; Mereu et al., 1987) and increases DA release
in the NAc (Imperato et al., 1986; Rahman et al., 2003).
Selective blockade of nAChRs in the VTA is sufficient to
prevent nicotine-induced DA release in the NAc,

918

Korpi et al.

nicotine-induced locomotion and nicotine SA (Nisell

et al., 1994). In rodents, when nicotine injections are
repeated, there is a sensitization of the nicotine-induced
locomotor activation (Clarke and Kumar, 1983; Ksir
et al., 1985) and the nicotine-induced NAc DA release
(Benwell and Balfour, 1992; Benwell et al., 1995;
Balfour et al., 1998; Schoffelmeer et al., 2002). Human
studies confirm a role for the DAergic system in the
effects of nicotine but paint a more complex picture. In
human PET studies, reduction of [11C]raclopride binding potential is used as an indirect measure of increase
in DA release. After nicotine administration by nasal
spray, there was no overall change in [11C]raclopride
binding in any striatal regions, but baseline [11C]
raclopride binding potential in the associative striatum
correlated negatively with the Fagerstrm score, an
index of nicotine dependence, and nicotine concentration correlated negatively with binding potential in the
limbic striatum (Montgomery et al., 2007a). However, in
tobacco-dependent individuals, smoking a regular cigarette resulted in greater reduction in ventral striatal
[11C]raclopride binding potential than smoking a denicotinized cigarette (Brody et al., 2009).
At higher doses, nicotine is aversive rather than
rewarding. Nicotine also often has aversive effects on
first exposure. Stronger aversive reactions in first-time
smokers are associated with reduced likelihood of development of habitual tobacco use (Sartor et al., 2010).
There is therefore increasing interest in understanding
the mechanisms of aversive responses to nicotine,
because aversive reactions on initial exposure may
reduce propensity to addiction. The MHb-IPN pathway,
which expresses a unique subset of a5, a3, and b4
nAChR subunits, has been implicated in aversive responses to nicotine (reviewed in Antolin-Fontes et al.,
2015) (see Fig. 10). In particular, a4b2a5* nAChR
subtypes have been implicated (reviewed in Fowler
and Kenny, 2014).
2. Upregulation of Nicotinic Receptors. Sustained
upregulation of nAChRs is a mechanism of nicotineinduced neuroplasticity that is likely of relevance to
nicotine addiction and which may contribute to some of
the sensitization effects observed on repeated nicotine
administration (reviewed in Govind et al., 2009). Generally, chronic exposure to agonists results in receptor
downregulation, whereas, chronic exposure to antagonists results in receptor upregulation. nAChRs are
remarkable in that exposure to the agonist nicotine can
cause long-lasting upregulation of nAChRs (see Fig. 9).
Comparison of brains of smokers and nonsmokers
revealed increased nicotine binding sites in the postmortem brains of smokers (Benwell et al., 1988; Breese
et al., 1997; Perry et al., 1999). Similar increases were
subsequently reproduced in the brains of mice and rats
after repeated nicotine administration (Marks et al.,
1983; Schwartz and Kellar, 1983; Yates et al., 1995;
Pietila et al., 1998). The upregulation does not appear to

involve increases in mRNA expression (Marks et al.,

1992) but rather reflects posttranscriptional mechanisms. The a4b2 nAChR subtype has fairly consistently
been implicated in nicotine-induced upregulation. In
vitro studies in fibroblast and HEK cell culture systems
expressing a4b2 nAChRs showed that nicotine exposure resulted in receptor upregulation as determined by
ligand binding (Peng et al., 1994; Bencherif et al., 1995;
Rothhut et al., 1996; Eilers et al., 1997; Gopalakrishnan
et al., 1997; Warpman et al., 1998; Whiteaker et al.,
1998; Harkness and Millar, 2002). Upregulation of
these subunits was further confirmed by transfection
of a4 and b2 subunits tagged with fluorescent protein
into both HEK cells and neurons from the ventral
midbrain (Nashmi et al., 2003). In vivo, upregulation
of a4 in response to nicotine treatment was shown in
a transgenic mouse expressing a4 tagged with yellow
fluorescent protein (Nashmi et al., 2007).
Replacement of b2 with b4 in receptors containing a4
or a3 reduces nicotine-induced upregulation assayed by
radioligand binding (Wang et al., 1998), whereas addition of a5 or b3 may block upregulation (Perry et al.,
2007; Mao et al., 2008). Association of a4b2 with a5 may
explain why nicotine-induced nicotinic receptor upregulation is not observed in some brain regions (Mao
et al., 2008). Chronic nicotine failed to induce nAChR
upregulation in the adrenal gland, which has little a4b2
nAChRs (Flores et al., 1997; Davila-Garcia et al., 2003).
Comparison of nicotine-induced upregulation of a3b2,
a4b2, and a6b2 nAChRs in transfected cells revealed
subtype differences in sensitivity to nicotine concentration and the time course of upregulation (Walsh et al.,
2008). a4b2 nAChRs were most sensitive, upregulating
at lower nicotine concentration, whereas a6b2 nAChRs
required higher concentrations of nicotine, and a3b2
nAChRs required the highest concentrations of nicotine. a6b2 nAChRs showed the fastest upregulation,
followed by a3b2 nAChRs, whereas a4b2 nAChRs
showed the slowest response. On chronic nicotine
exposure, a6b2* nAChRs are downregulated rather
than upregulated (Lai et al., 2005; Perry et al., 2007;
Doura et al., 2008; Marks et al., 2014). a6b2* nAChR
downregulation was more sensitive to the dose of
chronic nicotine treatment than a4b2* nAChR upregulation (Marks et al., 2014).
Thus, different receptor nAChR receptor subtypes
may respond differently to different doses, durations,
and patterns of nicotine exposure. For example, within
the VTA, it appears that chronic nicotine upregulates
a4* nAChRs on GABAergic neurons but not on DA
neurons (Nashmi et al., 2007). Similarly, in the SN,
chronic nicotine increased functional a4b2* nAChRs on
GABAergic neurons of the SN pars reticulata but not on
DA neurons of the SN pars compacta (Xiao et al., 2009).
It has been proposed that exposure to nicotine leads to
nAChR upregulation in the VTA, increasing excitability
and favoring induction of LTP resulting in sensitization

Drug-Induced Neuroplasticity

919

Fig. 9. Summary of the effects of acute (green) and chronic (red) nicotine on neuronal activities via different subtypes of nACh receptors in the ventral
tegmental area and the cortex/hippocampus. The nicotinic synapse depicts facilitatory actions of nicotine on presynaptic neurotransmitter release and
on postsynaptic LTP.

to the effects of DA leading to behavioral sensitization

and drug addiction (Govind et al., 2009). Further
studies are required to establish how the doses and
patterns of nicotine exposure associated with smoking
differentially regulate the various nAChR subtypes in
different brain regions.
Various mechanisms have been proposed to underlie
nicotine-induced upregulation of nAChRs. Importantly,
it was earlier shown that the mechanisms underlying
upregulation must be posttranslational rather than
transcriptional, because nicotine exposure did not alter
nAChR subunit mRNA levels (Marks et al., 1992).
Proposed mechanisms have included decreased turnover of receptors (Peng et al., 1994), desensitization of
surface receptors (Fenster et al., 1999), enhancement of
receptor maturation (Sallette et al., 2005), and slow
stabilization of receptors in a high-affinity state that is
more easily activated (Vallejo et al., 2005). However,
recent consensus of opinion, at least for upregulation of
a4b2* nAChRs, has converged on the notion that
nicotine acts as a pharmacological chaperone (Kuryatov
et al., 2005; Henderson et al., 2014; Srinivasan et al.,
2011, 2012). Pharmacological chaperoning of intracellular nAChRs is proposed to facilitate subunit assembly
in the ER and enhance export of assembled receptors
from the ER and their transport and insertion into the
membrane.
3. Nicotine-priming Effects and Upregulation of
Catecholamine Synthesis. Nicotine does not only sensitize or prime catecholaminergic systems via upregulation of nicotinic receptors, there is also evidence that
nicotine exposure sensitizes or primes certain catecholaminergic systems more directly by upregulating expression of TH, the rate-limiting enzyme for catecholamine

synthesis. Acute nicotine administration increased catecholamine synthesis in the NAc, hypothalamus, and HC,
whereas chronic administration of nicotine by daily subcutaneous injections in rats for 28 days potentiated this
response in the HC (Mitchell et al., 1989). This chronic
treatment increased TH activity in the HC (Joseph et al.,
1990). Studies of chronic treatment of 7 to 28 days showed
that the first increase in TH activity from 3 days in the
NEergic locus ceruleus (LC) and DAergic nuclei. Subsequently, the TH protein expression spread in the
NEergic projections to the forebrain, reaching the terminals up to 3 weeks later, consistent with axonal transport
of the enzyme from the cell bodies (Smith et al., 1991).
Subsequently, it was shown that 7-day treatment or even
a single injection of nicotine was sufficient to produce an
increase in TH activity in the terminal fields 34 weeks
later (Smith et al., 1991; Mitchell et al., 1993). A single
acute nicotine injection (0.8 mg/kg) was sufficient to
increase mRNA for TH in the LC cell bodies 2 to 6 days
later and, 4 weeks later, to increase TH activity in the
terminals and NE release in the hippocampus on challenge injection of nicotine (0.4 mg/kg) (Mitchell et al.,
1993).
NE is known to induce synaptic plasticity in the
hippocampal dentate gyrus (Neuman and Harley, 1983;
Stanton and Sarvey, 1985; Burgard et al., 1989; Dahl
and Sarvey, 1989; Harley, 1991, 1998, 2007), suggesting the possibility that nicotine-induced priming of
nicotine-induced NE release in the HC could induce
neuroplasticity. After priming with seven daily injections of nicotine, a challenge dose of nicotine produced
a long-lasting potentiation of medial perforant pathdentate gyrus evoked responses (Hamid et al., 1997).
This effect was blocked by both mecamylamine and

920

Korpi et al.

propranolol, indicating involvement of nAChRs and

b-adrenoceptors. Subsequently, it was shown that this
nicotine priming and challenge effect cross-primes with
other mechanisms, increasing TH expression in the LC.
Theta driving at 7.7 Hz, which is suggested to mimic
aspects of anxiety or stress responses, increased TH
activity in rat HC 15 to 33 days later (Graham-Jones
et al., 1985) and 0.4 mg/kg challenge injection of nicotine
induced medial perforant path-dentate gyrus longlasting potentiation in rats primed by theta driving
but not in rats that did not receive theta driving
(Markevich et al., 2007). Chronic clozapine treatment
activated the LC (Souto et al., 1979; Ramirez and Wang,
1986; Nilsson et al., 2005) and increased TH expression
in the LC (Verma et al., 2007). Rats primed with
clozapine (30 mg/kg) daily for 7 days showed nicotine
(0.4 mg/kg) challenge-induced medial perforant pathdentate gyrus long-lasting potentiation 21 to 28 days
later (Rajkumar et al., 2013). These data suggest that
nicotine alone or in conjunction with other stimuli can
induce TH expression in the LC, resulting in delayed
transport of TH to the afferent terminal fields facilitating nicotine-induced NE-mediated synaptic plasticity.
Nicotine may also induce synaptic plasticity within
catecholaminergic nuclei themselves.
4. Nicotine and Neuroplasticity within the Ventral
Tegmental Area. DAergic neurons of the VTA and SN
are tonically active, firing irregularly at low frequency,
but can switch to burst firing (Grace and Bunney,
1984a,b) (Fig. 9). The switch between tonic and burst
firing has been associated with signaling of novel events
and reward (Chergui et al., 1993; Cooper, 2002; Hyland
et al., 2002). A similar switch between tonic and burst
firing occurs in response to nicotine (Grenhoff et al.,
1986; Zhang et al., 2009). This burst firing is thought
to be mediated by activation of NMDARs on DAergic
cell bodies by glutamatergic afferents from the PFC
(Chergui et al., 1993; Tong et al., 1996). It is proposed
that stimulation of presynaptic a7 nAChRs on glutamatergic afferents (Jones and Wonnacott, 2004) releases
glutamate activating NMDARs on DAergic cell bodies to
produce the burst firing (Livingstone and Wonnacott,
2009). The activation of NMDARs not only induces acute
changes in firing but can induce long-lasting presynaptic
facilitation and postsynaptic NMDAR-dependent LTP,
resulting in sustained increases in the sensitivity of
the DAergic neurons to burst firing (Mansvelder and
McGehee, 2000; Mansvelder et al., 2002). Likely, these
mechanisms translate to behavioral nicotine-induced
increases in responsiveness to reward.
However, the essential role of presynaptic a7 nAChRs
in induction of burst firing is questioned by the observation that nicotine still triggers burst firing in a7-KO mice
(for discussion, see Livingstone and Wonnacott, 2009).
Meanwhile, the effect of nicotine on DAergic cell firing
mode is abolished in b2-KO mice (Mameli-Engvall et al.,
2006). The situation is further complicated by the effects

of nicotine on inhibition and excitability of the VTA. a7

nAChRs are also expressed by GABAergic neurons in
the VTA (Klink et al., 2001; Jones and Wonnacott, 2004).
A model integrating these data (McKay et al., 2007;
Livingstone and Wonnacott, 2009) proposes that nicotine
desensitizes a4b2 nAChRs on GABAergic interneurons
rapidly and preferentially (Wooltorton et al., 2003), thus
disinhibiting DAergic neurons while simultaneously activating a7 nAChRs on DAergic cell bodies and glutamatergic afferent terminals (Mansvelder and McGehee,
2000). It is suggested that b2* nAChRs on DAergic cell
bodies contribute by providing depolarization enhancing
excitability and thus bringing the cell closer to the
threshold to change firing patterns or to induce LTP
(Livingstone and Wonnacott, 2009).
The nicotinic control of DAergic firing is further
complicated by essential and complex roles of the
balance between activation and desensitization of
nAChR mechanisms (Picciotto et al., 2008). Although
activation and desensitization likely occur over too fast
a time scale to contribute directly to maintaining
nicotine-induced neuroplasticity, it is likely that this
balance plays a role in determining the conditions
permissive to induction of neuroplasticity. As mentioned earlier, chronic nicotine treatment upregulates
a4* nAChRs on GABAergic interneurons, but not on
DAergic neurons, of the VTA and on glutamatergic
terminals in forebrain. This is suggested to be sufficient
to explain tolerance of DAergic neuron firing in midbrain and sensitization of synaptic transmission in
forebrain (Tapper et al., 2004; Nashmi et al., 2007).
The role of a7 nAChRs remains more controversial.
Although most reports suggest that upregulation of a4*
nAChRs alone is sufficient to explain sensitization and
tolerance, others studying in vitro expression of human
nicotine receptors have suggested that functional inactivation of a4b2 nAChRs and a7 nAChRs but sustained inhibition of a3* nAChRs by chronic exposure to
nicotine contributes to tolerance (Olale et al., 1997).
In addition to the roles of nicotine receptors on
GABAergic interneurons versus DAergic neurons in
the VTA, effects of nicotine on AMPAR/NMDAR ratios
in VTA DA neurons have been implicated in nicotinic
regulation of VTA plasticity. Drugs of abuse, including
nicotine, were found to increase AMPAR/NMDAR ratios
in midbrain DA neurons (Saal et al., 2003). In the case of
nicotine, a single dose of 0.5 mg/kg i.p. was administered
to mice, and 2430 hours later AMPAR/NMDAR ratios
were increased in VTA DA neurons in midbrain slices
(Saal et al., 2003). Subsequent investigations reported
that increases in AMPAR/NMDAR ratios likely occur
via a7 or b2* nAChR-mediated mechanism (Gao et al.,
2010a) and can occur as fast as within 1 hour of a single
nicotine injection.
A recent study by Doyon et al. (2013) on rats adds
further complexity, as a single dose of nicotine dramatically reduced DA release compared with baseline in the

Drug-Induced Neuroplasticity

NAc for at least 15 hours. Furthermore, nicotinetreated animals made more responses for obtaining
alcohol solution during the first operant sessions. These
effects were blocked by dihydro-b-erythroidine (b2*),
but not by methyllycaconitine (a7*). Nicotine pretreatment enhanced bath-applied ethanol-mediated increase
in the frequency of sIPSCs from GABA neurons in the
VTA slices, which was also seen during bath application
of GABAA receptor BZ agonist diazepam. Importantly,
nicotine sensitivity of DA release was not affected at 15
hours after the nicotine pretreatment, and also the bath
applied nicotine similarly enhanced the frequency of
sIPSCs in slices from saline- and nicotine-treated
animals. Therefore, further mechanisms were examined. A glucocorticoid/progesterone receptor antagonist,
mifepristone (RU486), given systemically or intra-VTA
before nicotine, attenuated the increases in sIPSC
frequency and responses for alcohol solution and rescued the impaired ethanol-induced DA release.
Whether the nicotine effect is peripherally or centrally
initiated is not known. Interestingly, both acute and
chronic nicotine as well as acute morphine reduce the
release of GABA in the VTA of mice (Vihavainen et al.,
2008), whereas morphine after nicotine enhanced the
release. In summary, these findings suggest that nicotine can enhance the activity of VTA DA neurons via
multiple mechanisms, including by influencing the
function of GABA neurons.
5. Nicotine and Neuroplasticity in the Lateral
Hypothalamic Orexin System. The lateral hypothalamic orexin (hypocretin) system has also been implicated in mechanisms of addiction and drug-induced
neuroplasticity in the VTA (for discussion, see Baimel
and Borgland, 2012; Baimel et al., 2012). Orexin
signaling to the VTA promotes synaptic plasticity by
potentiating glutamatergic inputs to DA neurons.
Acute nicotine administration excited orexin-expressing
neurons in the lateral hypothalamus/perifornical area
(Huang et al., 2011) and dose dependently increased Fos
expression in these brain regions (Pasumarthi et al., 2006).
Chronic administration of nicotine by repetitive injection
over 1014 days altered expression of mRNAs for preproorexin and orexin receptors (Kane et al., 2001, 2001).
The OX1 (hcrt-R1) receptor antagonist, SB-334867
[N-(2-methyl-6-benzoxazolyl)-N-1,5-naphthyridin-4-yl
urea], reduced nicotine SA in animals on both fixed ratio
and progressive ratio schedules (Hollander et al., 2008).
Fixed ratio schedules are thought to measure drug
reinforcement, whereas progressive ratio schedules
are thought to measure motivation to obtain the drug.
Furthermore, infusion of SB-334867 into the insular
cortex also reduced SA on the fixed ratio schedule
consistent with the observation that tobacco smokers
with damage to the insula are more likely to quit
smoking without relapse and the recurrence of urges
to smoke (Naqvi et al., 2007). Systemic administration
of SB-334867 also prevented reduction of the threshold

921

for intracranial self-stimulation by nicotine (Hollander

et al., 2008). Together these data suggest that nicotine
may act via the orexin system to induce synaptic
plasticity in the VTA, thus modulating responses to
reward. Involvement of the orexin system raises the
question of effects of nicotine on feeding. Overall,
nicotine decreases food intake, but likely this is mediated by actions in the brain stem rather than the VTA,
because it is blocked by mecamylamine infusion into the
fourth ventricle (Guan et al., 2004).
6. Nicotine and Glutamatergic Neuroplasticity.
There are also numerous reports on nicotine-induced
neuroplasticity in the HC and cerebral cortex. For
example, investigations of the effects of nicotine agonists and antagonists on LTD induction in wild-type, a2-,
a7-, and b2-KO mice revealed that LTD-inducing stimulation releases ACh activating a7 nAChRs to suppress
LTD at hippocampal CA3-CA1 synapses, but this effect is
reversed by nicotine via a non-a7, non-a2, and non-b2
receptor mechanism (Nakauchi and Sumikawa, 2014). In
hippocampal slices from animals chronically treated with
nicotine, expression of a4* nAChRs on glutamatergic
terminals is increased, and acute exposure to nicotine
during tetanic stimulation increases induction of LTP in
medial perforant path (Nashmi et al., 2007) (Figs. 9 and
10). Meanwhile, in cultured hippocampal neurons, activation of presynaptic a4b2* nAChRs produced a glutamatergic neurotransmission-dependent enlargement of
postsynaptic dendritic spines (Oda et al., 2014). Chronic
treatment with nicotine (2 mg/kg/day s.c.) for 6 weeks
reversed beta-amyloid (Ab)-induced memory and hippocampal LTP deficits (Srivareerat et al., 2011) and chronic
stress-induced intensification of Ab-induced long-term
memory and synaptic plasticity deficits (Alkadhi, 2011;
Alkadhi et al., 2010, 2011). Although the interaction
between acetylcholine receptors (AChRs) and Ab is
complex, overall activation of AChRs can have protective
effects against Ab toxicity, leading to an interest in
developing a7 agonists for treatment of Alzheimers
disease (reviewed in Lombardo and Maskos, 2015).
In freely moving mice, acute nicotine administration
(1 mg/kg i.p.) induced medial perforant path-dentate gyrus
synaptic potentiation by a mechanism dependent on DA
receptors in the HC and activity of VTA neurons (Tang
and Dani, 2009). Adult rats trained to intravenously selfadminister nicotine 0.04 or 0.08 mg/kg per infusion,
achieving daily nicotine intakes of approximately 200
and 300 mg/kg, respectively, showed decreased cell proliferation and increased cell death in the dentate gyrus of
the HC (Abrous et al., 2002). Nicotine SA under extended
access (0.03 mg/kg/infusion, 21 hours/day for 4 days) with
intermittent periods of deprivation (3 days) for 14 weeks,
but not nicotine intake under limited access (1 hour/day
for 4 days), enhanced proliferation and differentiation
of hippocampal neural progenitors (Cohen et al., 2015).
Together these data represent evidence for effects of
nicotine on plasticity in cortical and hippocampal

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Korpi et al.

pathways, but it is less clear that this plasticity is of any

functional relevance to the persistent neuroplasticity
underlying behaviors associated with addiction. The
evidence for involvement in addiction is stronger for
midbrain pathways.
7. Nicotine and the Habenula. Among midbrain
pathways involved in nicotine addiction, the habenulointerpeduncular pathway has recently received considerable attention (Velasquez et al., 2014; Antolin-Fontes
et al., 2015). The mammalian habenula is located at the
posterior medial end of the dorsal thalamus next to the
third ventricle. The habenula is phylogenetically highly
conserved across vertebrates (Concha and Wilson, 2001;
Aizawa et al., 2005; Dadda et al., 2010) and connects
limbic forebrain nuclei with midbrain and hindbrain
nuclei (Sutherland, 1982). The MHb receives major
inputs from the septum through the stria medullaris
and has a major output to the IPN through the
fasciculus retroflexus, whereas the LHb makes a minor
contribution to this projection (Herkenham and Nauta,
1979; Swanson and Cowan, 1979; Qin and Luo, 2009).
The MHb-IPN tract highly expresses a-bungarotoxininsensitive nAChRs (Mulle et al., 1991), likely containing a4, and a5, a3, and b4 nAChR subunits encoded by
the CHRNA5-A3-B4 gene cluster (Aizawa et al., 2012;
Shih et al., 2014). This gene cluster has been linked with
increased nicotine consumption and dependence in
human genetics studies (Berrettini et al., 2008; Bierut
et al., 2008; Lips et al., 2010; Liu et al., 2010; Ware et al.,
2011). Consistent with these human genetic studies,
animal models indicate a role for the MHb-IPN pathway
in modulation of nicotine aversion and nicotine withdrawal (Salas et al., 2009; Fowler et al., 2011; Frahm
et al., 2011) (Fig. 10). Mice with null mutation of
Chrna5, the gene encoding for the a5 nAChR subunit,

showed a marked increase in nicotine intake that could

be rescued by expression of a5 subunits in the MHb
(Fowler et al., 2011). The b4 nAChR subunit is important for receptor activation. Asp398Asn mutation in the
a5 nAChR subunit is associated with increased tobacco
usage in humans (Bierut et al., 2008; Saccone et al.,
2009; Bierut, 2010), and a5 Asp398Asn was found to
interact closely with a b4 Ser435 residue important in
increasing nAChR currents (Frahm et al., 2011). In mice
overexpressing Chrnb4, the gene encoding for the b4
nAChR subunit, viral-mediated expression of a5
Asp398Asn subunits reduced nicotine aversion (Frahm
et al., 2011). In mice chronically treated with nicotine,
null mutations of the a2 and a5 subunits highly
expressed in the IPN reduced mecamylamine-induced
withdrawal, and in wild-type mice microinfusion of
mecamylamine into the Hb or IPN precipitated withdrawal (Salas et al., 2009). Moreover, lentiviral expression in the MHb of a gain-of-function Thr374Ile variant
of the b4 nAChR subunit associated with reduced risk of
smoking resulted in strong nicotine aversion in mice,
whereas expression of a loss-of-function Arg348Cys
variant failed to induce nicotine aversion (Slimak
et al., 2014). Nicotine-induced excitation of the MHb
neurons in mice was mediated by tachykinin NK1 and
NK3 receptors (Dao et al., 2014). In chronic nicotinetreated mice, intra-MHb infusions of NK1/3 antagonists
provoked withdrawal symptoms, suggesting that the
tachykinin receptors were in a sensitized state.
Although, as discussed above, the a5, a3, and b4
nAChR subunits that are strongly expressed in the Hb
are likely resistant to nicotine-induced upregulation;
nicotine produces persistent changes in the MHb and
the fasciculus retroflexus projection to the IPN through
selective neurotoxicity. Administration of high doses of

Fig. 10. Summary of the effects of nicotine on various brain regions, with a special reference to adolescent exposure and to neurotoxicity in the medial
habenula. DG, dentate gyrus; fr, fasciculus retroflexus; HC, hippocampus; IPN, interpeduncular nucleus; LH, lateral hypothalamus; MHb, medial
habenula; mPFC, medial prefrontal cortex; MPP, medial perforant path; NAc, nucleus accumbens; TH, tyrosine hydroxylase; VTA, ventral tegmental
area.

Drug-Induced Neuroplasticity

nicotine, continuous infusion of 5.72, 6.44, 7.13, 20.41,

and 43.1 mg/kg/day nicotine tartrate via osmotic minipump or intermittently at 11.32 mg/kg/day via once
daily subcutaneous injection over 5 days resulted in
neurodegeneration of the axons of the MHb neurons
that form the fasciculus retroflexus (Carlson et al.,
2001). More recent neurochemical investigations indicate that cholinergic neurons of the MHb are also
a major target of this nicotine-induced neurodegeneration (Ciani et al., 2005). Previously, rather than affecting the MHb, continuous administration of stimulants
amphetamine or cocaine had been found to cause
neurodegeneration in the LHb, which has a weaker
contribution to the fasciculus retroflexus (Ellison, 1992;
Carlson et al., 2000). It has been suggested that as the
fasciculus retroflexus is a phylogenetically primitive
tract carrying much of the negative feedback from
forebrain back onto midbrain reward circuitry; the
destruction of these descending control pathways by
drug binges could result in loss of forebrain control of
addictive behavior (Ellison, 2002). This is consistent
with the role for the MHb-IPN pathway in modulation of
nicotine aversion and nicotine withdrawal (see above).
It is not known whether human smokers show similar
neurotoxicity in the MHb-IPN pathway. It is also not
known whether there is any subsequent adaptive
neuroplasticity and functional recovery. An important
question that remains to be further addressed is the
extent to which this neurotoxicity in the MHb is reversible. Further investigations are needed to understand the implications for behavior and whether the
effects of the neurotoxicity are permanent. More recently, it has been found that repeated nicotine exposure in adolescent rats reduces MHb activity and
increases nicotine preference, suggesting that repeated
phases of nicotine exposure induce a functional switch
in the activity of MHb neurons in adolescent rats
leading to increased nicotine consumption (Lee et al.,
2015).
8. Long-term Sequelae of Adolescent Exposure to
Nicotine. It has been suggested that nicotine has
especially profound effects on neuronal networks (Fig.
10), in particular in the PFC, when exposure occurs
during adolescence (Goriounova and Mansvelder,
2012a,b). The onset of puberty is a period of significant
development of the emotional brain, including the midbrain DAergic nuclei, the hypothalamus, the NAc, the
striatum, and amygdala. In contrast, development of
the frontal cortical areas responsible for self-control and
decision-making lags behind, maturing throughout
adolescence and into adulthood (Sowell et al., 2003;
Giedd, 2004; Casey et al., 2005) (Fig. 4). Asynchronous
brain development may thus be responsible for the
characteristic traits of adolescence (Goriounova and
Mansvelder, 2012a), such as mood swings, impulsivity,
risk-taking, and susceptibility to peer influence in social
behavior (Orr and Ingersoll, 1995; Spear, 2000; Galvan

923

et al., 2006). Together, impulsivity, risk-taking, and

susceptibility to peer pressure can contribute to increased risk of onset of smoking in adolescents. Once
they smoke, adolescents appear more susceptible to
dependence at lower levels of cigarette consumption
(Colby et al., 2000; Kandel and Chen, 2000). Similarly,
in mice and rats there is increased vulnerability to
nicotine SA during early adolescence (Adriani et al.,
2002; Ahsan et al., 2014). It has been proposed that
adolescents may show this greater vulnerability to
nicotine addiction, because nicotine has greater positive
effects and smaller negative effects in adolescents than
adults (ODell, 2009). Moreover, the adolescent brain
appears to be exceptionally sensitive to nicotine-induce
neuroplasticity.
Acutely, smoking during adolescence is associated with
disruption of working memory and attention consistent
with reduced PFC activation (Jacobsen et al., 2005, 2007;
Musso et al., 2007). Moreover, smoking is a prospective
risk factor for impaired cognitive function in later life
(Cervilla et al., 2000; Richards et al., 2003), and adolescent tobacco use is associated with increased risk of
developing mental and behavioral problems, including
abuse of other drugs, later in life (Brown et al., 1996;
Johnson et al., 2000; McGee et al., 2000; Ellickson et al.,
2001; Brook et al., 2004). In rodents, adolescent animals
are more susceptible to nicotine-induced CPP than adults
(Vastola et al., 2002; Belluzzi et al., 2004; Shram et al.,
2006; Kota et al., 2009; Shram and Le, 2010; Brielmaier
et al., 2012; Ahsan et al., 2014). Moreover, nicotine
administration during, but not after adolescence, has
long-lasting effects on cognitive, emotional, and
addiction-related behaviors (Adriani et al., 2003, 2004;
Counotte et al., 2009, 2011; Iniguez et al., 2009). Together
these data point to the conclusion that adolescent nicotine
exposure has long-term effects on attention, cognition,
and emotional function in adulthood (Adriani et al., 2003;
Counotte et al., 2009, 2011; Goriounova and Mansvelder,
2012a,b).
A model synthesizing the data on effects of adolescent
exposure to nicotine on PFC in rodents (Goriounova and
Mansvelder, 2012a,b) proposes that, in the short-term,
adolescent nicotine exposure increases local inhibition
via nAChRs on GABAergic interneurons, while simultaneously decreasing glutamatergic excitatory inputs to
PFC neurons by increasing presynaptic mGlu2 expression. However, in the long-term, local inhibitory activity
normalizes, but there is a persistent and long-lasting
downregulation of presynaptic mGlu2 on glutamatergic
afferent terminals, resulting in increased excitability of
PFC pyramidal neurons associated with long-lasting
downregulation of synaptic short-term depression and
impaired attention. In rodents, the adolescent PFC is
especially sensitive to nicotine-induced changes in gene
expression (Schochet et al., 2005, 2008; Polesskaya et al.,
2007). In adolescence, exposure to nicotine increases
expression of immediate early genes used as functional

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Korpi et al.

markers of neuronal activation (Leslie et al., 2004;

Schochet et al., 2005) and dendritic expression of mRNA
for dendrin, a protein associated with synaptic plasticity
(Schochet et al., 2008). Meanwhile, chronic nicotine
exposure increases expression of a wide range of genes
involved in neurotransmission, signal transduction, and
synaptic architecture (Polesskaya et al., 2007), and repeated nicotine exposure leads to increased phosphorylation of ERK and CREB involved in neuroplasticity
(Brunzell et al., 2003). After adolescent nicotine exposure,
nAChR levels in the PFC, likely representing primarily
nAChRs on GABAergic interneurons, are elevated in the
short-term but return to normal by 5 weeks (Counotte
et al., 2012), whereas in contrast, mGlu2 receptors are
strongly downregulated at this time point (Counotte
et al., 2011). In rats, acute nicotine exposure during
adolescence reduced PFC LTP in response to timed
presynaptic and postsynaptic activity (tLTP) but subsequently increased this LTP in adulthood (Goriounova
and Mansvelder, 2012b). These changes in LTP could be
explained by the changes in mGlu receptors, because
activation of mGlu2 receptors mimicked the acute decrease in tLTP and blocking of mGlu2 receptors mimicked
the long-term increase in tLTP. Increases in glutamate
release in the PFC also occur in NMDAR antagonist
models of aspects of schizophrenia. NMDAR antagonistinduced increases in PFC glutamate release are associated with deficits in attention and loss of impulse control,
and these behavioral effects can be reversed by administration of an mGlu2/3 agonist (Pozzi et al., 2011). Administration of mGlu2 agonist also improved attention
performance in animals that had been exposed to nicotine
during adolescence (Counotte et al., 2011).
The effects of adolescent nicotine exposure on mGlu2
are not unique to the PFC. Long-lasting changes in
mGlu2 function after adolescent nicotine exposure have
also been reported in the VTA and NAc, where they
modulate the rewarding properties of nicotine (Helton
et al., 1997; Kenny et al., 2003; Kenny and Markou,
2004; Liechti et al., 2007; Counotte et al., 2011). In these
brain regions, activation of mGlu2/3 receptors reduces
SA of nicotine (Liechti et al., 2007), and these receptors
are thought to play a role in development of drug
dependence and manifestation of affective withdrawal
symptoms (Kenny and Markou, 2004). However, the
precise role of mGlu2 downregulation in the VTA-NAc
system in the mechanisms of increased vulnerability to
nicotine addiction after adolescent nicotine exposure
requires further elucidation.
Recent findings suggest that long-term cigarette
smoking in adulthood is associated with accelerated
cerebral cortical thinning (Karama et al., 2015). Various
degrees of cortical thinning may be associated with
a number of neuropsychiatric diseases, such as schizophrenia, depression, dementias, and fetal alcohol spectrum disorders, and with an increased risk for them
(Narr et al., 2009; Peterson et al., 2009; Zhou et al.,

2011; Byun et al., 2012), and accelerated cortical thinning

may be a normal physiologic phenomenon during adolescence and even associated with better neuropsychological
performance (Squeglia et al., 2013). However, smoking
increases the prevalence of Alzheimers disease (Barnes
and Yaffe, 2011), and, therefore, it is important that
smoking-induced cortical thinning seems to be at least
partially reversible, albeit very slowly. Further studies of
the mechanism and extent of nicotine-induced structural
changes in the adult brain will likely be informative.
There is a strong association between habitual smoking and alcohol dependence, and there may be common
genetic risk factors (Bierut et al., 2000; Grucza and
Bierut, 2006; Mingione et al., 2012; Vrieze et al., 2013;
Anantharaman et al., 2014) (reviewed in Sturgess et al.,
2011). In particular, patients with chronic pain may be
susceptible to tobacco, alcohol, and opioid dependence
(Fishbain et al., 2012), and there is a strong association
between smoking and chronic pain (reviewed in Ditre
et al., 2011; Parkerson et al., 2013). Meanwhile, antidepressants have been used in treatment of alcohol
addiction, and antidepressants and MAO inhibitors
have been used in chronic pain management. It has
also been noted that MAO inhibitors increase tolerance
to alcohol in mice (Popova et al., 2000), and that tobacco
smoke exposure increases alcohol consumption in adolescent C56BL/6 mice (Burns and Proctor, 2013). Acetaldehyde is produced in high concentrations when
cigarettes are burned. There appear to be synergistic
interactions between acetaldehyde and both nicotine
and alcohol. Rats preferred a combination of acetaldehyde and nicotine to either substance alone (Rabinoff
et al., 2007). Moreover, rats could be trained to selfadminister acetaldehyde and subsequently consumed
more alcohol (Amit and Smith, 1985). Although most
alcohol metabolism occurs in the liver, some alcohol is
metabolized to acetaldehyde by microbial action already in the oral cavity. Deficient oral hygiene, heavy
alcohol drinking, and smoking modify oral microbiome
to increase acetaldehyde from local alcohol metabolism
(reviewed in Salaspuro, 2007). The acetaldehyde produced in this way may contribute not only to association
between smoking and alcohol dependence but also to
increased risk of gastrointestinal tract cancers.
9. Conclusions. Nicotine addiction leads to increased risk of severe adverse health effects caused by
tobacco. Distribution of nAChRs with different subunit
combinations in various brain regions contributes
to diverse mechanisms of plasticity. Mechanisms of
nicotine-induced plasticities include upregulation and
downregulation of nAChRs; interactions with catecholaminergic, GABAergic, and glutamatergic neurotransmission; and neurodegenerative structural changes in
fasciculus retroflexus and cortex. The extent to which
the changes induced by nicotine exposure are reversible
remains incompletely understood. There is need for
further investigation of the long-term sequalae of

Drug-Induced Neuroplasticity

nicotine exposure, particularly those of adolescent exposure. These mechanisms and relevant brain pathways
are summarized in Fig. 10. Nicotine addiction is of
particular concern because of the ready availability of
legally available tobacco products in many societies.
There is increasing evidence that early exposure to
nicotine leads to increased risk of later life dependence
not only on nicotine but also to other drugs of abuse
including alcohol. There is need for further investigation
of the mechanisms by which nicotine-induced plasticity
can increase risk of dependence to other drugs of abuse.
D. Neural Adaptations Induced by Ethanol
Ethanol is one of the most widely used psychoactive
substances worldwide, with both reinforcing and
sedative-hypnotic properties. Acutely, these effects
arise from many molecular targets, and they most
prominently involve alterations in synaptic function.
Repeated ethanol exposure leads to homeostatic
changes in synaptic and intracellular functions. Behaviorally, these neuroadaptations are expressed as tolerance, dependence, somatic withdrawal symptoms upon
cessation of chronic ethanol exposure, and so-called
protracted withdrawal characterized by susceptibility
to negative reinforcement that is postulated to contribute to relapse and compulsive features of ethanol
addiction. Figure 11 depicts the cycle of alcohol
intoxication/neural adaptation/withdrawal effects in
the brain, with proposed roles of the neurotransmitter/
modulator systems. In the following, we will focus
primarily on the synaptic effects of ethanol and their
persistent alterations in key brain regions during
chronic ethanol administration.
Adjunct pharmacological means to treat alcoholism
have been expanded from one specific drug, disulfiram,
to opioid receptor antagonists naltrexone and nalmefene and to glutamate receptor antagonists acamprosate (Heilig and Egli, 2006). Benzodiazepine therapy
during alcohol withdrawal is still important, especially
to protect the brain from potential neurotoxicity of
withdrawal-induced seizures (Sellers et al., 1983;
Walker et al., 2013). Recent neurobiological research
on ethanol addiction, relapse, and withdrawal has
produced many other potentially efficient drug targets,
which are mentioned below within a discussion on
mechanism of alcohol action and addiction.
1. Cell Membrane Ion Channels as Primary Targets
of Ethanol. Compared with many other drugs of abuse
that exert their actions through specific neurotransmitter
receptors or transporters, ethanol is a relatively nonspecific and nonpotent pharmacological agent. Ethanol
was believed to fluidize membrane lipids and cause
intoxication by perturbing neuronal function (for reviews,
see Deitrich et al., 1989; Franks and Lieb, 1994; Peoples
et al., 1996; Spanagel, 2009). Then, protein targets
emerged for anesthetics and for alcohols of various carbon
chain lengths (Franks and Lieb, 1984). A general binding

925

pocket for ethanol has not been settled, although in

several ligand-gated ion channels the action of alcohol is
dependent on specific single amino acid residues, as
modeled in a prokaryotic member of ligand-gated ion
channels, GLIC (Howard et al., 2011). Although many
drug targets have been revealed by using high-affinity
(nanomolar) radiolabel binding to brain membranes or
recombinant receptors, with ethanol this approach has
not been possible because of its 1000- or even 100,000-fold
lower affinity. However, there is accumulating evidence
that ethanol has a few well-defined molecular targets
(Trudell et al., 2014). At intoxicating ethanol concentrations, from low to approximately 100 mM, the most
important targets of ethanol include ion channels,
neurotransmitter receptors, and intracellular signaling
molecules. The best characterized of these targets are
ligand-gated ion channels (Lovinger and Roberto, 2013)
that bind extracellular neurotransmitters, which leads to
opening of an intrinsic ion pore.
In short, there are three major classes of ion channels
activated by neurotransmitters. The so-called cys-loop
channels are protein pentamers that have a Cys-Cys
bond in the N-terminal binding domain, four transmembrane domains forming the ion channel, and an
intracellular loop between TM3 and TM4 for modification by phosphorylation/dephosphorylation. This major
class of receptor channels passes either anions, such as
the g-aminobutyric acidA (GABAA) and strychninesensitive glycine receptors, or cations, such as the
nicotinic acetylcholine nACh and serotonin 5-HT3
receptors. The general action of acute ethanol is to
enhance the function of cys-loop ligand-gated ion channels (Lovinger, 1997; Harris, 1999; Perkins et al., 2010),
although ethanol can also produce inhibition in some
subtypes/receptor domains (Johnson et al., 2012). Ethanol exerts its action by potentiating channel opening in
the presence of low agonist concentrations. This is
achieved either by increasing the probability of channel
opening or increasing the agonist affinity (Tonner and
Miller, 1995; Zhou et al., 1998; Welsh et al., 2009).
The potentiation of the GABAA receptor by ethanol
has been investigated widely. The GABAA receptor is
assembled as variable combinations of 19 subunit
proteins (Collingridge et al., 2009), and many subunit
combinations have been characterized in heterologous
expression systems and in native receptor preparations,
including cultured and isolated neurons. In summary,
ethanol potentiates the function of various GABAA
receptor subtypes containing a, b, and g subunits, as
well as those containing a4 and a6 together with b and d
subunits (McCool et al., 2003; Olsen et al., 2007; Lobo
and Harris, 2008). In brain slices from the cerebellum,
HC, and thalamus, ethanol potentiation has also been
observed in extrasynaptic, d subunit-containing highaffinity GABAA receptors mediating a tonic inhibitory
current (Wei et al., 2004; Hanchar et al., 2005; Glykys
et al., 2007; Jia et al., 2008). However, the potentiation

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Korpi et al.

Fig. 11. The effects of alcohol are shown with a distinction between acute and withdrawal phases, with alcohol drinking during them inducing positive
and negative reinforcement, respectively. Each state is associated with specific effects and symptoms mediated by specific neurobiological mechanisms.
The summary illustrates some of the most important alcohol targets and their adaptations during chronic alcohol exposure. Modified from Littleton
(1998).

has not been universally replicated in all neuron types

or experimental settings (Borghese et al., 2006; Korpi
et al., 2007; Lovinger and Homanics, 2007). Ethanolinduced potentiation of GABAA receptor function may
also depend on protein phosphorylation. For example,
the epsilon subunit of protein kinase C (PKC) appeared
to be necessary for ethanol potentiation of GABAA
receptors containing the g2 subunit (Qi et al., 2007),
whereas PKCd was required for ethanols action on the d
subunit-containing GABAA receptors (Choi et al., 2008).
It is noteworthy that ethanol potentiation of GABAergic
inhibition often results from presynaptic actions of
ethanol. Ethanol enhances GABA release from presynaptic terminals, which contributes to synaptic inhibition
(for reviews, see Siggins et al., 2005; Lovinger and
Roberto, 2013). These data are obtained mostly from
brain slices and isolated neurons from the cerebellum,
HC, VTA, and amygdala (Ariwodola et al., 2003; Roberto
et al., 2003; Kelm et al., 2007; Theile et al., 2008). The
mechanism of ethanol enhancement of GABA release is
not well established, but ethanol may interact with
mechanisms involved in intracellular calcium release,
increasing presynaptic calcium concentrations (Kelm
et al., 2007). The possible role of intracellular signaling
pathways in this ethanol effect is suggested by findings
that GABA release is diminished in cerebellar Purkinje
neurons by PKA inhibitors and in the CeA in mice lacking
PKC (Bajo et al., 2008; Kelm et al., 2008).
Ethanol potentiation of the strychnine-sensitive glycine receptor channels also depends on the receptor
subunit composition. Greatest potentiation is seen in a1

subunit-containing receptors in the Xenopus leavis

oocytes (Valenzuela et al., 1998b), whereas receptors
with the a2 subunit are less sensitive (Mascia et al.,
1996). Expression of the b subunit together with a2
abolishes ethanol potentiation (McCool et al., 2003). As
both the GABAA and glycine receptors are inhibitory,
ethanol enhancement of their function increases neuronal inhibition. The net effect on neural networks is
determined by the primary target, either interneurons
or principal neurons. Intracellular mechanisms for the
glycine receptor potentiation by ethanol have been
revealed, e.g., in isolated VTA neurons (Ye et al., 2001;
Zhu and Ye, 2005). The activated G protein bg-subunits
enhance the ethanol effect in recombinant glycine
receptors by binding to specific intracellular domains
[including two lysines at 385/386) of the a1 subunits
(Yevenes et al., 2003, 2008)]. Knock-in mice with the
LysLys385/386AlaAla mutation in the a1 subunits
exhibited reduced alcohol intoxication (shorter duration
of loss of righting reflex) and almost complete lack of
potentiation by 100 mM ethanol in isolated brain stem
neurons and cultured spinal cord neurons (Aguayo et al.,
2014). Presynaptic glycine receptors can reduce GABA
release in the VTA, which can activate DA neurons (Ye
et al., 2004). In addition to GABA release, ethanol also
augments glycine release via Ca2+-dependent mechanisms (Mariqueo et al., 2014). Strychnine blocks the
ethanol-induced DA release from the nucleus accumbens
and attenuates nicotine- and THC-induced release, but
not the release induced by cocaine and morphine (Jonsson
et al., 2014), indicating the importance of glycine

Drug-Induced Neuroplasticity

receptors in the modulation of mesolimbic DA pathway

activity.
Acute ethanol also potentiates the function of serotonin 5-HT3 receptors that gate an intrinsic cation
channel (Lovinger and White, 1991; Machu and Harris,
1994). As these receptors are expressed both pre- and
postsynaptically, the site of ethanol action remains to be
determined. The roles of the five different 5-HT3 receptor subunits (Thompson, 2013) are not well elucidated. Interestingly, in rat brain, the 5-HT3 receptors
have been localized primarily to cholecystokinincontaining (CCK) GABAergic interneurons (Morales
and Bloom, 1997). Furthermore, they are also expressed
in vagal afferents from the stomach, where they can be
activated by serotonin released from enterochromaffin
cells, which together with the area postrema 5-HT3
receptors participate in nausea and/or emesis reflexes
(Hornby, 2001).
Like the GABAA receptor, the nACh receptor is often
composed of multiple subunits (see section II.C on
nicotine), but homomeric receptors also exist. High
ethanol concentrations (.100 mM) potentiate the majority of nACh receptor subtypes without selectivity
(Narahashi et al., 1999; Zuo et al., 2002). However, the
effects of ethanol concentrations lower than 100 mM are
dependent on the a subunit, with potentiation of a2b4,
a4b4, a2b2, and a4b2 nACh receptors, with no effect on
a3b4 and a3b2 receptors, and inhibition of the a7
receptors. In chimeric recombinant homomeric receptors with the N-terminal ligand-binding domain from
the nACh a7 subunit and the rest from 5-HT3A subunits, nicotine responses were inhibited by ethanol
similarly to a7 receptors, suggesting that the ethanol
inhibition was dependent on the N-terminal ligand
binding domain (Yu et al., 1996).
The second major class of ligand-gated ion channels
consists of the ionotropic glutamate receptors (iGluRs)
that have three major subclasses, the AMPARs, the
NMDARs, and the kainate receptors (Collingridge et al.,
2009). All these subclasses are cation permeable, but
differ in selectivity between Na+, K+, and Ca2+. These
ligand-gated receptor channels are homo- or heterotetramers, with subunits having large N-terminal ligandbinding domains, three TM regions, and a fourth re-entrant
loop as in potassium channels. Although ethanol partially
inhibits all iGluRs, inhibition of NMDARs with intoxicating ethanol concentrations has been most extensively
investigated (Dildy and Leslie, 1989; Hoffman et al., 1989;
Lovinger et al., 1989; Kuner et al., 1993; Moykkynen and
Korpi, 2012). Functional NMDARs are heteromers, containing two glycine-binding GluN1 subunits combined
with two glutamate-binding GluN2 subunits (A-D) or with
two GluN3 subunits. The GluN3 subunit has been poorly
characterized in native receptors, but it may be important
for synaptic plasticity especially during development
(Ulbrich and Isacoff, 2008; Pachernegg et al., 2012; Kehoe
et al., 2013). Ethanol inhibits all NMDAR subtypes, but in

927

recombinant receptors the sensitivity to inhibition

depends on the subunit composition. Ethanol slightly
more efficiently inhibits the GluN1/2A- or GluN1/2Bcontaining receptors than receptors with GluN1/2C subunit composition (Kuner et al., 1993; Masood et al., 1994;
Chu et al., 1995). There are several splice variants of the
GluN1 subunit, and the splicing status of this subunit
may affect ethanol sensitivity, depending on the identity
of GluN2 subunit in the receptor (Jin and Woodward,
2006). Among AMPARs (composed of GluA1-4 subunits),
non-GluA2 receptors are calcium permeable (Burnashev
et al., 1992). Although ethanol also inhibits the AMPARs,
higher concentrations are needed than for the inhibition of
the NMDARs, and their subunit composition does not play
a major role in determining ethanol sensitivity (Lovinger,
1993; Frye and Fincher, 2000). Ethanol produces the
inhibition by promoting desensitization of the AMPARs
(Moykkynen et al., 2003). The kainate receptors (composed of GluK1-5) are inhibited by ethanol at low concentrations, but it is unclear whether this action involves
direct effects on the receptor protein (Valenzuela et al.,
1998a; Lack et al., 2008). The GluK1 receptors are
especially interesting, because the presence of a polymorphism in GRIK1 gene correlated with a robust response to
topiramate in reducing heavy drinking of alcoholdependent subjects (Kranzler et al., 2014). Taken together, inhibition of the iGluRs by ethanol decreases
neuronal excitability and also inhibits synaptic plasticity
that requires activation of iGluRs.
The purinergic trimeric P2X receptors constitute the
third major class of ligand-gated ion channels. At intoxicating concentrations, ethanol has inhibitory effects on
many P2X subtypes, with the P2X4 receptors being the
most sensitive subtype to inhibition (Li et al., 1993;
Davies et al., 2002, 2005). Interestingly, inhibition of
the ATP action on native P2X receptors or recombinant
rat P2X4 receptors by series of alcohols provides evidence
for a cut-off point at butanol, allowing smaller alcohols to
inhibit presumably via binding to a binding pocket of
a restricted size (Li et al., 1994; Asatryan et al., 2010). The
anthelmintic agent ivermectin has a positive allosteric
action at this subtype, among several other ligand-gated
ion channels, such as GABAA receptors (Zemkova et al.,
2014). Ivermectin reduces alcohol drinking in mouse
models (Yardley et al., 2012, 2014). Further functional
significance of ethanol actions on P2X1/3 receptors comes
from findings that ethanol reduces GABA release in
isolated VTA DA neurons via inhibition of ATP effects
on P2X receptors (Xiao et al., 2008).
Also the nonligand-gated ion channels are targets
of ethanol. Ethanol inhibits high-voltage-activated
dihydropyridine-sensitive Ca 2+ channels (L-type,
Cav1.x) (Wang et al., 1994) and potentiates the function
of G protein-activated inwardly rectifying K+ channels
(GIRKs, Kir3.x) (Kobayashi et al., 1999; Lewohl et al.,
1999), which both inhibit neural activity. The
large conductance Ca2+- and voltage-activated K+ (BK)

928

Korpi et al.

channel has emerged as a most interesting molecular

target for ethanol, based on genetic studies on Caenorhabditis elegans and Drosophila, and on recent results
from mouse knockout and human genetic association
studies (Treistman and Martin, 2009; Bettinger and
Davies, 2014; Dopico et al., 2014). BK channels are also
involved in neuroadaptation to alcohol. They are formed
as tetrameric complexes from two a subunits and two b
subunits (usually either b1 or b4), and they are
expressed throughout the body; in the brain they are
present in all areas with presynaptic and extrasynaptic
compartments. Ethanol usually activates these channels
in neurons, which should produce neuronal inhibition
and reduction in neurotransmitter release depending on
the b subunits. Tolerance to ethanol appears in minutes
as reduced channel sensitivity, followed by declustering
and internalization of the channels. The b1 subunits
make the BK channels insensitive to ethanol, while b4
subunits provide ethanol sensitivity (Feinberg-Zadek
et al., 2008). This seems to correlate in mouse models
with quicker escalation of limited access alcohol drinking
after induction of dependence by chronic intermittent
ethanol inhalation in the absence of the b1 subunit
(Kreifeldt et al., 2013) and quicker tolerance development
to motor impairment in the absence of the b4 subunit
(Martin et al., 2008). The search for the site of action of
ethanol and other n-alcohols on BK channel-forming a
subunits is very actively pursued (Bukiya et al., 2014;
Davis et al., 2014). The discovery of this site of action
might allow the rational development of an alcohol
antagonist for BK channels. In addition, establishing
more detailed roles of the accessory b subunits in the
regulation of channel function by phosphorylation (Liu
et al., 2006) might open novel ideas for translational
experiments.
Ethanol may also affect the function of the GPCRs,
but generally these effects by acute ethanol are weak
and the mechanisms are unclear, unlike those of opioids
and cannabinoids acting on their respective GPCRs.
There is early evidence that ethanol can stimulate
cAMP production, perhaps by activating ACs, which
can underlie ethanol-induced neurotransmitter release
(Luthin and Tabakoff, 1984; see above for discussion on
GABA release).
2. Ethanol-Induced Changes in Glutamatergic
Transmission. Repetitive patterned activation of afferent inputs to postsynaptic neurons induces longlasting changes in the efficacy of synaptic transmission.
The most common forms of these changes, LTP and
LTD, have also been examined after acute ethanol
(McCool, 2011). Consistent with the inhibition of
NMDARs at relevant ethanol concentrations, acute
ethanol inhibits induction of LTP at various synapses
and experimental preparations, such as Schaffer collateral inputs to the CA1 pyramidal neurons in the HC
(Zorumski et al., 2014). Acute ethanol also modulates
types of LTD in many brain regions, including LTD in

the HC involving activation of mGluRs (Overstreet

et al., 1997) and the eCB-mediated signaling in the
dorsal striatum (Clarke and Adermark, 2010). Ethanol
inhibition of these types of plasticity is consistent with
acute ethanol-induced impairment of working and
short-term memory (Schweizer and Vogel-Sprott, 2008).
Considering the development of alcoholism in humans,
however, the most relevant neural changes recapitulated
by animal models probably include those produced by
chronic ethanol exposure. Chronic ethanol produces
tolerance, manifested by decreased behavioral response
to ethanol, and dependence, characterized by a specific
symptomology after ethanol withdrawal. In addition,
chronic alcohol exposure can also produce a postdependent state, which is understood as a combination of
behavioral and neuroadaptive consequences that are
produced as the individual becomes dependent and which
remain for extended periods even in the absence of the
drug-specific withdrawal symptoms. Typical behavioral
correlates of the postdependent state include anxiety,
dysphoria, and exaggerated stress responses (Heilig and
Koob, 2007).
Various experimental paradigms have been used for
inducing alcohol dependence, including repeated
intraperitoneal or intragastric administration, ethanolcontaining liquid diets, and either continuous or intermittent ethanol vapor chamber exposure. These
paradigms typically produce peak blood ethanol concentrations of 3569 mM (150300 mg/dl), which cannot
be attained by most voluntary ethanol drinking models.
However, alcohol-preferring mice consume enough ethanol to achieve blood ethanol levels exceeding 23 mM
(100 mg/dl) in the recently described binge-drinking
model (drinking in the dark) (Rhodes et al., 2005), and
the reintroduced intermittent ethanol access model
results in escalation of ethanol drinking in rats, with
intoxicating blood ethanol levels (Wise, 1973; Simms
et al., 2008). Even if induction of alcohol dependence in
these binge models is debatable, long-term binge drinking has been shown to produce a variety of neuroadapations (Stuber et al., 2008; Wilcox et al., 2014).
Chronic ethanol increases NMDAR function at both
synaptic and extrasynaptic compartments in many
brain regions and experimental preparations. Enhanced NMDAR function is seen as an increased intracellular level of NMDAR agonist-induced Ca2+ or
directly as increased ion current through the NMDAR
pore (Gulya et al., 1991; Iorio et al., 1992; Smothers
et al., 1997; Grover et al., 1998; Floyd et al., 2003).
However, the ability of acute ethanol to inhibit
NMDARs is not diminished by chronic ethanol treatment (Roberto et al., 2004b). The mechanism underlying the enhanced NMDAR function is not well known,
but it may involve increases in the levels of the GluN2B
subunit (Floyd et al., 2003; Carpenter-Hyland et al.,
2004; Kash et al., 2009). In the VTA, chronic ethanol has
also been associated with a higher order plasticity,

Drug-Induced Neuroplasticity

described as metaplasticity, that affects synapses of

postsynaptic neurons in a global manner, increasing
their susceptibility to undergo activity-dependent LTP/
LTD (Abraham, 2008). Thus, chronic ethanol enhances
the susceptibility of VTA DA neurons to the induction of
LTP of NMDAR-mediated transmission. This plasticity
results from an increase in the potency of inositol 1,4,5trisphosphate (IP3) in producing amplification of action
potential-evoked Ca2+ signals, lasting for 1 week after
ethanol exposure (Bernier et al., 2011). This kind of
metaplasticity could be an important neuroadaptation
that drives the formation of drug-associated cues both
during drug intoxication and withdrawal.
Acute doses of many drugs of abuse, including
ethanol, increase the AMPAR/NMDAR current ratio
in VTA DA neurons (Saal et al., 2003), reflecting an
enhancement of AMPAR-mediated excitatory synaptic
transmission. The findings of the chronic ethanol effects
on AMPARs are sparse and variable, suggesting
increases in AMPAR expression in the HC (Bruckner
et al., 1997) and increased AMPAR function, as shown
by enhanced AMPAR-mediated synaptic responses in
the BLA (Lack et al., 2007). In the VTA neurons,
voluntary intermittent ethanol consumption enhances
postsynaptic AMPAR function without altering presynaptic glutamate release (Stuber et al., 2008). The
enhanced AMPAR function in the BLA could contribute
to drug seeking, whereas in the VTA, AMPAR activity
could regulate firing of the mesolimbic DA neurons and
thereby contribute to the reinforcing and activating
effects of ethanol.
In the NAc, another key component of the reward
circuitry, glutamatergic innervation, interacts with the
mesolimbic DA system and participates in drug reinforcement, drug seeking, and relapse. The Homer
proteins are integral components of the PSD that
appear to be necessary for alcohol-induced neuroplasticity within the NAc. For example, chronic ethanol
consumption under continuous access produces a robust
increase in the NAc Homer2 protein levels, which was
observable even 2 months after withdrawal from alcohol
drinking (Szumlinski et al., 2008). The increased
Homer2 expression was accompanied by elevation in
total mGlu1 receptor and GluN2B subunit levels during
the first 2 weeks after withdrawal. Furthermore, both
virus-mediated knockdown of Homer2 expression and
intra-NAc antagonism of mGlu5 and PI3K attenuated
ethanol intake, suggesting that upregulation of NAc
mGlu5-Homer2-PI3K signaling constitutes an important neuroadaptation to chronic ethanol (Cozzoli et al.,
2009).
Chronic ethanol produces elevated extracellular glutamate levels in the brain, especially during withdrawal
and repeated cycles of withdrawal, thus contributing to
the hyperglutamatergic state implicated in the development of ethanol dependence. These findings have
been derived from both in vivo microdialysis and

929

magnetic resonance spectroscopy studies (Rossetti and

Carboni, 1995; Hermann et al., 2012), and they do not
directly indicate whether the source of glutamate is
synaptic, extrasynaptic, glial, or metabolic. However,
there is evidence of increased synaptic glutamate release from the CeA after chronic ethanol treatment,
pointing to adaptations in the presynaptic terminal
function (Roberto et al., 2004b).
3. Ethanol-Induced Changes in g-Aminobutyric Acidergic Transmission. GABAergic neurotransmission is
one of the primary targets of ethanol and is hypothesized to be involved in multiple long-lasting neuroadaptations underlying ethanol tolerance, dependence,
and reinforcement. Many early studies focused on
elucidating changes in the expression profiles of specific
GABAA receptor subunits by chronic ethanol, with the
hypothesis that these changes could account for alterations in the functional properties of GABAergic signaling after chronic ethanol exposure (Kumar et al.,
2009). Generally, these studies failed to show dramatic
changes in the number of GABAA receptors across the
preclinical models, but pointed to a number of regionspecific and temporally dependent alterations in
GABAA receptor subunit mRNA and peptide levels
(reviewed in Uusi-Oukari and Korpi, 2010). For example, in the cerebral cortex, chronic ethanol consumption
elicited an increase in a4 subunit mRNA levels and
a decrease in a1 subunit mRNA levels. There was also
an increase in g2S, but not g2L, subunit mRNA levels
after chronic ethanol consumption. In addition, g1
subunit expression was increased, whereas a5, b1, b2,
b3, g3, and d subunit mRNA levels did not change
(Devaud et al., 1995). These changes correlated well
with the receptor subunit peptide levels in ethanoldependent rats, but not necessarily with subunit expression during withdrawal (Devaud et al., 1997). However,
other brain regions did not exhibit similar patterns of
subunit changes, and subregions of the cerebral cortex
differed from the whole cortex (Grobin et al., 2000). Direct
comparison of cerebral cortex and HC revealed that also
in the HC the a4 subunit peptide level was increased,
but a1, a2, a3, b2/3, or g2 subunits were not altered,
suggesting that chronic ethanol changes GABAA receptor
gene expression in the HC but differently from that in the
cerebral cortex (Matthews et al., 1998). Moreover, the
changes were dependent on the length of ethanol exposure. Recent data from human postmortem brain areas
from controls and alcoholics have also revealed brain
region-specific changes in GABAA and glutamate receptor subunit expression in alcoholics (Jin et al., 2011;
Bhandage et al., 2014; Jin et al., 2014a,b).
The hypothesis derived from the adaptive changes in
the GABAA receptor expression by chronic ethanol is that
those adaptations lead to a hypofunction of GABAergic
synaptic functions, expressed as tolerance and increased
neuronal excitability during ethanol withdrawal, which
forms the basis for the treatment of severe alcohol

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Korpi et al.

withdrawal with benzodiazepines (Sellers et al., 1983).

There is evidence that ethanol-induced alterations in the
expression of GABAA receptor subunits leads to diminished GABAA-mediated transmission. For example,
chronic intermittent ethanol exposure induces a decrease
in a1 and d subunits and an increase in a4 subunit in rat
HC. These changes were reflected in recordings made in
hippocampal slices from ethanol-exposed animals. Thus,
the decay time of GABAA-mediated miniature IPSCs was
decreased and potentiation of these current by positive
modulators was reduced by chronic ethanol, except for
the a4-preferring benzodiazepine ligands, with which
potentiation was either maintained or even increased
(Cagetti et al., 2003). Synaptic and extrasynaptic components of GABAA receptor activation were investigated in
the same animal model and hippocampal preparation.
After chronic ethanol, potentiation of tonic current by the
a1 subunit-preferring agonist zolpidem was lost, whereas
potentiation by the a4 subunit-preferring THIP was only
partially reduced. Also the potentiation of synaptic
GABAA receptor currents by zolpidem was eliminated
by chronic ethanol, whereas THIP enhanced them after
ethanol exposure. These data are consistent with a1
subunit decreases in both synaptic and extrasynaptic
compartments, and with increased a4 subunits in synaptic and decreased a4 subunits in extrasynaptic GABAA
receptors (Liang et al., 2004). The cause for these changes
is not clear, but one possibility is that the putative
primary reduction in a1 expression leaves the g2 subunit
(that is needed for synaptic targeting) available to
assemble with a4 subunits, which increases the synaptic
a4 subunit-containing receptors. In these receptors, the
inverse agonist of the benzodiazepine-site Ro 15-4513
acts as an agonist [like in a6 subunit-containing receptors
of the cerebellar granule neurons (Malminiemi and
Korpi, 1989)] and enhances the synaptic responses only
in the ethanol-dependent rats (Liang et al., 2006).
The CeA, a major component of the extended amygdala, has emerged as an important brain area for both the
acute positive reinforcement of drugs of abuse and
negative reinforcement associated with protracted abstinence. Ethanol drinking in nondependent rats is
inhibited by antagonism of GABAA receptors in the CeA
(Hyyti and Koob, 1995), whereas GABAA activation
modulates ethanol reinforcement only in animals after
chronic ethanol exposure (Roberts et al., 1996), suggesting altered CeA GABAergic transmission by chronic
ethanol. Acute ethanol augments GABAA-mediated inhibition in the CeA, which can be at least partially
mediated by ethanol-induced presynaptic GABA release
(Roberto et al., 2003). In CeA slices from rats treated
chronically with ethanol, the baseline evoked IPSPs and
IPSC amplitudes were increased and the paired-pulse
facilitation ratios were lower than in naive rats, consistent with increased GABAergic transmission involving
postsynaptic effects after chronic ethanol treatment.
Ethanol administered in vitro enhanced IPSPs and

IPSCs similarly in slices from ethanol-naive and

ethanol-dependent rats, suggesting that tolerance did
not develop to this acute effect of ethanol. The frequency
of miniature IPSCs was higher in chronically ethanoltreated rats, in line with the idea that enhanced
GABAergic transmission both by acute and chronic
ethanol could also be ascribed to a presynaptic mechanism involving vesicular GABA release. Verification with
microdialysis showed a fourfold increase in baseline
GABA release in ethanol-treated rats compared with
controls (Roberto et al., 2004a), although this method
cannot necessarily distinguish between neuronal and
glial GABA release. Significant GABA release seems to
take place from glial cells (astrocytes) that may have
a GABAergic phenotype (Lee et al., 2011) and release
GABA via bestrophin 1 anion channels (Lee et al., 2010).
These data show that both acute and chronic ethanol
effects on GABAergic transmission could involve pre- and
postsynaptic alterations. More recently, ethanol-induced
increase in firing rates of subpopulations of CeA neurons
has been shown to be mediated by CRF1 receptors and
tonic GABA currents, with the network effect being
increased output neuron activity to the BNST (Herman
et al., 2013), a brain region involved in sustained anxiety
and relapse. Furthermore, the ethanol-induced increase
in GABA release and IPSC amplitudes in the CeA slices
can be blocked by activation of presynaptic CB1 receptors
(Roberto et al., 2010a), demonstrating multiple presynaptic mechanisms being involved in ethanol modulation
of amygdala activity.
Further evidence for involvement of presynaptic
mechanisms in ethanol effects on GABAergic transmission has been obtained from the VTA. A single
ethanol dose induced a long-lasting facilitation of GABA
transmission, as suggested by paired-pulse depression
in ethanol-treated animals compared with paired-pulse
facilitation in controls (Melis et al., 2002). Also, as the
frequency of spontaneous miniature IPSCs was increased, a presynaptic mechanism can be inferred.
Indeed, a GABAB antagonist shifted paired-pulse depression to paired-pulse facilitation, indicating presynaptic GABAB receptor activation by hypothesized
GABA spillover by ethanol treatment. Similarly in the
VTA, a single ethanol exposure increased GABA release
onto DA neurons (Wanat et al., 2009). The importance of
these cellular, possibly long-lasting signaling events for
ethanol consumption and development of addiction
remains to be investigated. In contrast to GABA
neurotransmission in the amygdala, chronic alcohol
treatment makes the VTA GABA system hyposensitive,
which may be based on persistent changes in gene
expression (Arora et al., 2013).
Dorsal striatum and associated sensorimotor structures have been implicated in the development of addiction, particularly in the mediation of habit formation, and
this region has also emerged as a site of alcohol-induced
neuroadaptations. In cynomolgus monkeys, prolonged

Drug-Induced Neuroplasticity

intermittent alcohol drinking decreased the frequency of

GABAA receptor-mediated miniature IPSCs recorded
from the MSNs in the caudoventral area of the putamen
(Cuzon Carlson et al., 2011). This area corresponds to the
dorsolateral striatum in rodents, and a similar reduction
of IPSC frequency was produced by repeated binge
drinking in mice in this striatal area, but also in the
dorsomedial striatum (Wilcox et al., 2014). These data
suggest that heavy, long-term alcohol exposure causes
a depression of GABAergic transmission in the dorsal
striatum, contributing to an increased output from this
structure.
4. Ethanol-Induced Changes in Neuropeptide
Mechanisms. Various neuropeptide systems have
been hypothesized to be recruited or downregulated
during chronic ethanol exposure. Particularly in the
extended amygdala, neuropeptides may underlie the
negative emotional states that contribute to compulsive
ethanol seeking and drinking via negative reinforcement (Koob, 2008).
CRF plays a role in coordinating hormonal, autonomic, and behavioral stress responses in the body.
In ethanol-dependent animals, ethanol withdrawal
increases CFR levels in the CeA and BNST (Merlo Pich
et al., 1995; Olive et al., 2002). Administered into the
CeA, a CRF antagonist attenuated ethanol withdrawalrelated anxiety (Rassnick et al., 1993). Increased ethanol consumption during protracted abstinence after
induction of ethanol dependence was reduced by selective CRF1 receptor antagonism, but in nondependent
animals CRF antagonist failed to modulate ethanol
intake, suggesting that CRF contributes to increased
ethanol consumption induced by dependence (Funk
et al., 2007). CRF1 and CRF2 receptors mediate their
most physiologic functions in the brain via coupling
to heterotrimeric Gas-proteins and activating AC
(Grammatopoulos, 2012). Increased cAMP levels then
turn on a plethora of cytoplasmic (e.g., activation of
PKA) and nuclear (e.g., nuclear factor k-light-chainenhancer of activated B cells (NFkB), ERK1/2, and
GSK-3B/Wnt signaling) functions. Also, activation of the
PLC-PKC pathway has been implicated in the dose dependently increasing effects of CRF on VTA DA neuron
firing (Wanat et al., 2008). In midbrain slices from bingedrinking mice, CRF-potentiation of NMDAR responses
was found in VTA DA neurons, and the binge drinking
was significantly reduced by intra-VTA infusion of CRF1
receptor antagonist CP-154526 [N-butyl-N-ethyl-2,5dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]
pyrimidin-4-amine hydrochloride] (Sparta et al., 2013).
In the CeA, ethanol-induced enhancement of GABAergic
transmission is mediated by CRF1 receptors, perhaps
even by CRF release, as shown by lack of ethanolstimulated GABA release in CRF1 receptor-KO mice
and after CRF1 but not CRF2 receptor antagonists (Nie
et al., 2004). Moreover, CFR1-mediated ethanol effects
on GABA in the CeA involve activation of the PKC

931

pathway (Bajo et al., 2008). In CeA slices of ethanoldependent rats, the sensitivity of GABA release on
CRF and CFR1 antagonists was increased, and in vivo
intra-CeA administration of a CRF1 antagonist reversed dependence-related elevations in baseline extracellular GABA and blocked ethanol-induced increases
in GABA in both dependent and nondependent rats.
Chronic treatment with a CRF1 antagonist blocked
withdrawal-induced increase in alcohol drinking in
ethanol-dependent rats (Roberto et al., 2010b). Collectively, these findings suggest a specific chronic ethanolinduced synaptic neuroadaptation in the interaction of
CRF and GABAergic transmission that could contribute
to the development and maintenance of ethanol dependence, together with other described functional
alterations in the CeA (Hansson et al., 2006; Sommer
et al., 2008). Also the BNST has a rich expression of
CRF, and the region is well connected with many brain
regions, including the midbrain DA neurons and the
CeA. In the juxtacapsular nucleus of the anterior BNST,
a form of LTP in response to HFS of the stria terminalis
was impaired during withdrawal from chronic ethanol,
and this impairment was reversed by CRF1 receptor
antagonism (Francesconi et al., 2009). Therefore, also
the BNST CRF system may undergo persistent changes
during development of ethanol dependence. Novel
modulators have been found to play a role in reinstatement of alcohol drinking, because blockade of the
relaxin-3 receptor RXFP3 by intra-BNST infusion of
an antagonist attenuated cue- and stress-induced reinstatement of alcohol drinking in rats (Ryan et al.,
2013). Importantly, the neurons in the brain stemlocated nucleus incertus, which is the major source of
relaxin-3 in the mammalian brain, are highly sensitive
to stress and CRF (Banerjee et al., 2010; Smith et al.,
2011; Farooq et al., 2013).
Another relevant peptide neurotransmitter system
uses orexin A/hypocretin-1 and orexin B/hypocretin-2
peptides that are synthesized selectively in the lateral
hypothalamus, perifornical area, and dorsomedial hypothalamus (de Lecea et al., 1998; Sakurai et al., 1998),
with the lateral hypothalamus orexin system being
most strongly associated with rewarding behaviors
(Harris et al., 2005, 2007). In the VTA, both orexins
and CRF have similar excitatory effects on DA neurons
(Borgland et al., 2010). Orexin effects are mediated by
OX1 and OX2 receptors, which mainly couple to Gq/11
and PLC-PKC pathways. Both receptor subtypes appear to be expressed in various neuronal populations of
the VTA, and both DA and GABA neurons increased
their firing rates by orexins (Korotkova et al., 2003). The
OX1 receptor is expressed on VTA DA neurons. Its
stimulation induces increased membrane targeting of
the NMDARs, thereby potentiating their currents
(Borgland et al., 2006). Importantly, initial findings on
the effects of OX1 receptor antagonists suggest that they
do reduce alcohol drinking in some, but not all,

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Korpi et al.

paradigms in rodent models (Lawrence et al., 2006;

Moorman and Aston-Jones, 2009; Dhaher et al., 2010;
Jupp et al., 2011; Voorhees and Cunningham, 2011).
Further work is needed to establish the ways by which
orexin antagonists could be useful in the treatment of
alcohol abuse and other drug addictions. The OX1 and
OX2 receptor antagonists have very strong effects on
arousal and they thus might be emerging as the future
generation of hypnotic drugs for insomnia (Michelson
et al., 2014), provided they pass safety screening, such
as possible induction of narcolepsy, which is related to
deficiency of orexin and its receptors (Thannickal et al.,
2000).
Other neuropeptides that have been shown to modulate the interaction of ethanol with GABAergic neurotransmission in the CeA include neuropeptide Y (NPY)
and nociceptin/orphanin FQ (N/OFQ). NPY mediates
many behavioral responses to ethanol (Thiele et al.,
1998), and NPY injections into the CeA suppress
ethanol drinking, particularly in ethanol-dependent
animals (Gilpin, 2012). Superfusion of NPY decreased
baseline CeA GABAergic transmission and reversed
ethanol-induced enhancement of inhibitory transmission by suppression of GABA release through presynaptic Gi/o-coupled Y2 receptors (Gilpin et al., 2011). NPY
is anxiolytic and may mediate acute ethanol-induced
anxiolysis. By using histone deacetylase inhibitors,
Sakharkar et al. (2012) showed in alcohol-preferring P
rats that a rapid tolerance is produced to this anxiolytic
effect during chronic ethanol treatment via possible
epigenetic changes causing a reduction in NPY expression. It is quite possible that these epigenetic changes
are far more frequent and affect the transcription of
many genes important for plasticity (Nestler, 2014) and
that epigenetic mechanisms can also contribute to
genetic vulnerability to increased alcohol consumption,
at least in animal models (Moonat et al., 2013).
Also the effects of the peptide nociception/orphanin
FQ (N/OFQ) on GABAergic transmission are altered by
chronic ethanol. N/OFQ decreases CeA GABAergic
transmission by reducing GABA release, and this
N/OFQ-induced decrease was more pronounced in
ethanol-dependent rats (Roberto and Siggins, 2006).
N/OFQ is the endogenous ligand of the Gi/o-coupled
N/OFQ (NOP) receptor, also referred to as the opioid
receptor-like 1 receptor. Because N/OFQ has been
shown to attenuate many ethanol-related behaviors,
including cue- and footshock stress-induced ethanol
seeking and anxiety during ethanol withdrawal (Witkin
et al., 2014), there has been a growing interest to test
brain penetrating NOP receptor agonists for their effects
on ethanol drinking. Recently, a novel NOP agonist, MT7716 ((R)-2-{3-[1-(acenaphthen-1-yl)piperidin-4-yl]-2-oxo2,3-dihydro-1H-benzimidazol-1-yl}-N-methylacetamide
hydrochloride hydrate), was shown to reduce ethanol
drinking persistently even for 1 week after discontinuation of the drug and to attenuate ethanol somatic

withdrawal symptoms (Ciccocioppo et al., 2014), presumably by inhibiting presynaptically GABA and glutamate release, as shown in the amygdala slices
(Kallupi et al., 2014a,b). Furthermore, presumably via
presynaptic mechanisms, NOP activation counteracts
the CRF-induced increase in GABAA receptor-mediated
IPSPs in the CeA slices from naive rats and even more
robustly in ethanol-dependent rats (Cruz et al., 2012),
suggesting that dependent animals have developed sensitized responses to NOP activation in the
amygdala.
A large body of evidence suggests that the endogenous
opioid system is involved in the behavioral actions of ethanol. Acute ethanol stimulates the release of the endogenous opioid peptides b-endorphin, enkephalin, and
dynorphin in the brain (Gianoulakis, 2001), and m- and
d-opioid receptor antagonists decrease ethanol SA
and seeking in many experimental models (Koob
et al., 2003), suggesting that the Gi/o-coupled, mainly
presynaptic, m- and d- receptors are involved in the
mediation of the positive reinforcing effects of ethanol.
These results have been translated into the treatment
of alcoholism by using nonselective opioid receptor
antagonists, naltrexone or nalmefene, to block alcohol
reward either chronically or on demand (Volpicelli et al.,
1992; Hyytia and Sinclair, 1993; Mann et al., 2013).
Dynorphin, an endogeneous ligand of the Gi/o-coupled
k-receptors is linked to aversive states, and accumulating data implicate the dynorphin/k-receptor system in
the processes of negative reinforcement in ethanoldependent subjects (Sirohi et al., 2012). In animals
chronically exposed to ethanol, both the predynorphin
mRNA and dynorphin B expression was increased in
the NAc (Przewlocka et al., 1997; Lindholm et al., 2000),
suggesting an upregulation of the k-receptor/dynorphin
system during ethanol dependence, although the
k-receptor mRNA level was decreased (Rosin et al.,
1999). The fact that either intracerebroventricular,
intra-accumbal, or intra-amygdalar administration of
k-receptor antagonists selectively suppressed ethanol
SA in dependent animals with no effect in nondependent subjects (Walker and Koob, 2008; Nealey et al.,
2011; Kissler et al., 2014) suggests that the upregulated
k-receptor/dynorphin system contributed to escalation
of ethanol intake after dependence induction. The functional consequences of the alteration in the k-receptor/
dynorphin system are not known, but increased signaling through the k-receptors was shown to reduce DA
release locally in the NAc (Spanagel et al., 1992) and in
the PFC terminal area via inhibition of VTA DA
neurons (Margolis et al., 2006), possibly leading to
dysphoric and depression-like behavioral states. The
transcriptional processes underlying these events
may include the CREB that mediates the increases in
the dynorphin levels in the mesolimbic DA system
(reviewed in Sirohi et al., 2012). One of the important
targets of CREB is the BDNF that modulates dynorphin

Drug-Induced Neuroplasticity

expression (Lonze and Ginty, 2002). Ethanol exposure

increases BDNF expression in the dorsal striatum,
which could lead to initiation of MAP kinase signaling
and a subsequent increase in the downstream gene
products, including preprodynorphin (McGough et al.,
2004; Logrip et al., 2008). This could be one of the
mechanisms contributing to the hypothesized dysregulation of the dynorphin signaling linked with ethanol
dependence (Walker and Koob, 2008).
Ghrelin is a circulating gut-brain hormone that
promotes food consumption through hypothalamic
growth hormone secretagogue receptors (GHS-R1A)
(Horvath et al., 2001). In addition to the role of ghrelin
in body weight regulation, it has also been suggested to
be involved in mediation of the reinforcing effects of
drugs, including alcohol (Jerlhag et al., 2009). For
example, GHS-R1A antagonists suppress alcohol intake
in many animal models of alcohol SA, and a recent study
demonstrated that no tolerance developed to repeated
antagonist administration (Suchankova et al., 2013).
The GHS-R1A receptors are also widely expressed in
the mesocorticolimbic DA system, and the VTA expression of Ghsr was downregulated in the rats drinking
high amounts of alcohol compared with the lowdrinking individuals (Suchankova et al., 2013). Similar
to ghrelin, other gut-brain hormones have also been
implicated in the regulation alcohol drinking, including
glucagon-like peptide 1, leptin, and galanin (Blednov
et al., 2004; Lewis et al., 2004; Egecioglu et al., 2013).
Also histamine has been as a gut-based mediator of
smooth muscle function and a central neurotransmitter
that participates in regulation of food intake (among
a wide variety of important CNS roles), and recently it
has been shown to modulate alcohol consumption and
alcohol-induced place preference via H3R histamine
receptors (Panula and Nuutinen, 2013).
5. Role of Acetaldehyde in Ethanols Reinforcing
Actions. Although it is widely believed that the actions
of the ethanol molecule itself are responsible for ethanol
reinforcement, there is evidence to suggest that ethanol
metabolism and its products, particularly acetaldehyde,
could have a role in ethanol consumption and abuse
(reviewed in Quertemont, 2004; Deng and Deitrich,
2008; Deehan et al., 2013). The bulk of ethanol is
metabolized in the liver by alcohol dehydrogenase and
aldehyde dehydrogenase (ALDH) enzymes. Alcohol dehydrogenase is not physiologically active in the brain.
However, the first metabolic product, acetaldehyde, can
also be formed in the brain through the peroxidative
activity of catalase and by oxidation via other enzymes,
such as the cytochrome P450 2E1. Significant acetaldehyde concentrations are formed in vitro in brain tissue
at concentrations of ethanol achieved from voluntary
consumption by rodents.
Although there are many demonstrations of the
reinforcing actions of acetaldehyde in the brain, either
by experimenter- or self-administered acetaldehyde

933

(Deehan et al., 2013), the mechanisms of action remain

to be clarified. Converging evidence suggests that
acetaldehyde could contribute to ethanols stimulatory
action on the VTA DA neurons. Acetaldehyde stimulates VTA DAergic activity at remarkably lower concentrations than ethanol in vitro (Brodie and Appel,
1998; Diana et al., 2008), and in vivo a catalase inhibitor
applied in the VTA prevents ethanol-stimulated increase in DAergic activity (Melis et al., 2007; Diana
et al., 2008). Further support for the involvement of
catalase and acetaldehyde in ethanols central actions
comes from studies using viral vectors altering catalase
activity. For example, introduction of an anticatalase
viral vector into the VTA decreased ethanol drinking
and ethanol-induced DA release in the NAc (Karahanian
et al., 2011; Quintanilla et al., 2012). However, the DAreleasing effect of ethanol in the NAc is not mediated by
acetaldehyde (Clarke et al., 2014). It is also to be noted
that acetaldehyde is a highly reactive molecule that
interacts with many endogenous substances in the brain
to form additional biologically active products (Deehan
et al., 2013).
Acetaldehydes putative central reinforcing actions
notwithstanding, peripheral acetaldehyde is aversive.
This is amply demonstrated by the ALDH blocking drug
disulfiram (Antabuse, Odyssey Pharmaceuticals, East
Hanover, NJ) that causes increased accumulation of
acetaldehyde and thereby highly aversive effects
shortly after ethanol consumption, thus curbing further
drinking. In some Asian populations, the ALDH2*2
allele that encodes an inactive form of the mitochondrial
ALDH2 enzyme, has a high prevalence. Individuals
homozygotic for ALDH2*2 exhibit high blood acetaldehyde concentrations even after light to moderate alcohol
drinking, and it has been shown that this allele strongly
protects against alcoholism (Quertemont, 2004).
6. Structural Plasticity in Alcohol Dependence.
Because dendritic spines are both structural and functional units of excitatory synapses and include many
critical postsynaptic components of the synapse, any
changes in spine number or morphology could have
long-reaching consequences for the connectivity of
neural networks. Similar to other drugs of abuse
(reviewed in other sections), chronic ethanol regulates
the spine dynamics in many brain areas important for
learning, memory, reward, executive function, and
stress (reviewed in Cui et al., 2013). The general picture
emerging from these studies is that chronically administered ethanol decreases many measures related to
dendrites and their spines, accompanied by functional
or behavioral alterations. For example, withdrawal
from long-term ethanol exposure decreases spine density in the amydgala, concomitant with increased
anxiety and decreased BDNF-Arc signaling (Pandey
et al., 2008). In the NAc, both chronic alcohol drinking
and alcohol withdrawal decreased spine density, accompanied by reduction in NMDAR-mediated synaptic

934

Korpi et al.

currents and hampered LTD (Zhou et al., 2007; Spiga

et al., 2014). On the other hand, prolonged intermittent
alcohol drinking in cynomolgus monkeys increased the
density of dendritic spines and glutamatergic transmission in the putamen, but not in the caudate nucleus
(Cuzon Carlson et al., 2011). Similarly, chronic intermittent alcohol exposure increased spine density in the
mPFC in mice (Kroener et al., 2012). These findings
suggest that the direction of alcohol-induced alterations
in dendritic spine plasticity is dependent on brain
region. The functional consequences of these structural
alterations in the brain networks remain to be
elucidated.
It is noteworthy that some structural changes seen in
ethanol exposure in adult animals can also be seen if
ethanol treatment has been given during the prenatal
period. Prenatal ethanol treatment retarded the growth
of the SN pars compacta TH-positive neurons and
produced abnormalities in dendritic branching (Shetty
et al., 1993). In the forebrain, ethanol exposure produced a sexually dimorphic effect on dendritic branching in the NAc and reduced spine density and
distribution in the PFC (Lawrence et al., 2012). In
humans, heavy ethanol consumption during pregnancy
produces fetal alcohol spectrum disorders, of which the
most severe form is the fetal alcohol syndrome. Although
it is accepted that high ethanol doses can produce
detrimental effects on brain development, the mechanisms remain elusive. Data from animal models suggest
that mechanisms of ethanol action on the developmental
trajectory of neural cells include alterations in many
neurotransmitter and signaling systems, neural migration, neurogenesis, and synaptic plasticity (Valenzuela
et al., 2012).
7. Conclusions. Ethanol exerts its acute and chronic
effects via a number of molecular targets, altering
synaptic transmission, brain function, and behavior
(Fig. 11). Acutely, ethanol increases synaptic and
extrasynaptic inhibition by enhancing GABAergic
mechanisms and decreases excitation by inhibiting
NMDARs. The net effect of these neurochemical events
is dampening of synaptic excitation, which also either
hampers or modulates various forms of synaptic plasticity. Chronic ethanol exposure leads to compensatory
homeostatic effects in these neurotransmitter systems.
Thus, the function of the NMDARs is enhanced and
extracellular glutamate levels are elevated, contributing to neuronal hyperexcitability implicated in ethanol
dependence and withdrawal. Chronic ethanol effects on
GABAergic transmission lead to a hypofunction of
GABAergic systems. Particularly in the extended amygdala, chronic synaptic neuroadaptations involve interactions of the GABAergic neurotransmission with various
neuropeptides that either mediate or counteract ethanolinduced alterations. The between-systems adaptations
could contribute to the development of ethanol dependence and mediate the interactions between stress,

anxiety, and chronic ethanol effects. In addition, these

neuropeptide systems could be important future targets
for pharmacological treatment of alcoholism.
E. Benzodiazepines and Other GABAergic Drugs
Benzodiazepines (BZs) were introduced to clinical use
as anxiolytics in the 1960s, and soon they displaced
barbiturates and similar compounds as safer and more
efficient anxiolytics and hypnotics. BZs were acutely
well-tolerated and patients are usually compliant with
the therapy. Unfortunately, anxiety did not always
vanish. Soon, problems with their use emerged as some
patients developed tolerance, and in many users
attempts to withdraw from the medication lead to
a return of the initial anxiety symptoms. This apparently led to a strong urge for continued use, with, in
some patients, considerable difficulty in cutting down
chronic BZ medication and possibly a negative effect on
concurrent cognitive therapy (e.g., Westra and Stewart,
1998; Vorma et al., 2002). Whether BZ therapy persistently affects cognitive functions has been difficult to
assess. For example, Puustinen et al. (2007) found no
association of cognitive impairment (assessed with
Mini-Mental State Examination) with long-term use of
BZs in a nonrandomized study comparing patients
admitted to acute hospital wards during 1 month with
and without BZ treatment, whereas a small metaanalysis found significant impairments (Barker et al.,
2004a). The long-term BZ effect was clearer when the
reversal of cognitive impairment in different domains of
neuropsychological tests was monitored during withdrawal from prolonged BZ use (Barker et al., 2004b).
The results showed significant reversal during abstinence, which was not quite complete in comparison with
the scores in controls or normative data. Recently,
several epidemiologic studies reported increased risk
of dementia symptoms in older BZ users (Billioti de
Gage et al., 2015), with the risk increasing with
cumulative dose and treatment time. Causality of the
association is not yet known, because BZ drugs may also
have some protective effect against Alzheimers disease
(Fastbom et al., 1998) or be associated with insomnia
and increased risk for this disease (Chen et al., 2012).
BZs are still used in clinical medicine as anxiolytics,
sedatives, and hypnotics, although guidelines have
suggested that their use in anxiety disorders should
be indicated only in severe cases that do not respond to
certain antidepressants (particularly serotonin selective reuptake inhibitors), gabapentin/pregabalin, or
psychotherapy (Baldwin et al., 2014). BZ-site acting
hypnotics, preferably short-acting ones, should be prescribed for shorter treatment periods with careful
tapering off the dosages. Antihistamines and melatonin
should be tested for insomnia and a2-adrenoceptor
agonists or anesthetics be used for sedating agitated
and aggressive patients before using BZs. Furthermore,
nonpharmacological therapies, such as exposure and

Drug-Induced Neuroplasticity

cognitive psychotherapies, may provide good results for

many patients with less severe insomnia (Hofmann and
Smits, 2008).
Like all other abused drugs, only a portion of patients
will show increase in tolerance and develop troublesome
dependence during BZ therapy. Therefore, these efficacious drugs should not be fully forgotten (e.g., see
Starcevic, 2014). Therefore, it is important to understand their mechanisms of action and their long-term
effects on brain structure and function. In this section,
we will also shortly review the effects of related drugs,
such as GABAB agonists, g-hydroxybutyrate (GHB),
and anesthetetic agents.
1. Molecular Targets for Benzodiazepines. The
GABAA receptor is the main fast-acting inhibitory
neurotransmitter receptor in the mammalian brain
(for reviews for molecular biology and receptor subtypes, genetics, structure, and function, see Sieghart,
1995; Whiting et al., 1995; Olsen and Sieghart, 2008,
2009; Uusi-Oukari and Korpi, 2010). It is a pentameric
integral plasma membrane ligand-gated ion channel,
assembled from 19 different subunits (a1-6, b1-3, g1-3,
d, , u, p, and r1-3), which are products of different genes
residing in several clusters in the human and rodent
genomes (Olsen and Sieghart, 2008). Most GABAA
receptors have the subunit structure of 2a22b2g/d.
Subunits are heterogeneously expressed in various
brain cell types and regions, thus producing pharmacologically and functionally different GABAA receptor
subtypes (Wisden and Seeburg, 1992; Luddens et al.,
1995; Hevers and Luddens, 1998; Korpi et al., 2002;
Sigel and Steinmann, 2012), and some of them are
produced in alternative spliced or RNA edited isoforms.
Positive BZ-site modulators, such as diazepam, midazolam, and zolpidem, typically need the a and g
subunits for their allosteric actions increasing affinity
of GABA binding (Sigel, 2002). The most important site
of the receptor molecule for BZ binding is the 100th
residue of the a subunits, which is histidine (His) in all
diazepam-sensitive receptors with a1, a2, a3, and a5
subunit-containing receptors and arginine in diazepaminsensitive a4 and a6 subunit-containing receptors
(Luddens et al., 1995). This residue was originally
detected in an abnormal subunit a6 (Luddens et al.,
1990; Wieland et al., 1992), with restricted expression to
cerebellar granule neurons. Receptors with this subunit
do not bind diazepam but bind an inverse agonist
imidazobenzodiazepine Ro 15-4513, correlating with
the pharmacological profile of the cerebellar granule
cell layer (Sieghart et al., 1987; Malminiemi and Korpi,
1989; Uusi-Oukari and Korpi, 1990; Turner et al., 1991).
Furthermore, a spontaneous mutation changing arginine (Arg) to glutamine (Gln) was detected in the
cerebellar a6 subunit of alcohol-sensitive, and particularly BZ-sensitive, ANT rat line (Korpi et al., 1993;
reviewed in Korpi et al., 2007). Glutamine behaved
in the receptor similarly as histidine, drastically

935

increasing the receptor sensitivity to benzodiazepines

for binding and positive allosteric modulation (Korpi
et al., 1993). These observations were extended by Uwe
Rudolph, Hanns Mhler, and colleagues by using His to
Arg knock-in mutations for understanding the roles of
various BZ-sensitive GABAA receptors in the behavioral
and physiologic effects of diazepam in mouse models
(Table 2 with the references). Importantly, in mice,
these findings suggested that anxiolytic actions could be
separated from sedative actions, because the former
effects were absent in a2(His101Arg) knock-in mice,
whereas the a1(His101Arg) mice exhibited limited
sedative effects of diazepam (Low et al., 2000) or even
hyperactive phenotype after a sedative dose of diazepam (McKernan et al., 2000). These mouse models have
also indicated that tolerance and dependence-inducing
effects of diazepam are dependent on a1 and a5 subunitcontaining receptors (van Rijnsoever et al., 2004; Tan
et al., 2010). All these effects are also associated with g2
subunit-containing receptors, because this subunit is
obligatory for BZ binding (Pritchett et al., 1989).
Because the g2 subunit gives the subcellular address
for GABAA receptors to be trafficked into inhibitory
synapses (Essrich et al., 1998), all these knock-in mouse
models are related to BZ actions on phasic synaptic
inhibition.
More recently, the focus has moved to extrasynaptic
GABAA receptors, which usually contain the d subunit
instead of g2, with preferential expression together
with either a6 (in cerebellum) or a4 (in forebrain)
subunits (Wisden et al., 1992; Jones et al., 1997). These
receptors do not form high-affinity BZ binding sites (but
see Wallner et al., 2006), but they form a receptor
population with high GABA sensitivity, low conductance, and slow desensitization, and their main function
is to provide tonic extrasynaptic inhibition regulated by
ambient GABA (Mody, 2001; Stell and Mody, 2002;
Farrant and Nusser, 2005). When this kind of tonic
inhibition is abolished from the cerebellar granule cells
by genetically knocking out the a6 subunit, it is compensated by increased expression of two-pore leak K+
channels of TASK-1 type (Brickley et al., 2001). For these
neurons, it has been estimated that the charge transfer
via tonic inhibition is at least 10 times greater than that
via phasic synaptic inhibition (Brickley et al., 1996),
further indicating the physiologic importance of tonic
inhibition. The d subunit-containing receptors have high
affinity to GABA-site agonists muscimol and gaboxadol,
which are less potent in inducing behavioral effects in
GABAA d-KO mice (Chandra et al., 2010). Also, the effects
of neurosteroid agonists, such as ganaxolone, are reduced
in d-KO mice (Mihalek et al., 1999).
The peripheral BZ receptor (PBR) has been detected
in many tissues using the same BZ ligands as for
GABAA receptors. The PBR is now known to be the
mitochondrial translocator protein (TSPO), which is
believed to be particularly involved in cholesterol

936

Korpi et al.

transport into inner mitochondrial matrix for the initial

step of steroidogenesis by P450 side chain-cleavage
enzyme producing pregnenolone (reviewed in Rupprecht
et al., 2010). TSPO-KO from testicular Leydig cells,
however, failed to affect steroidogenesis (Morohaku
et al., 2014). In the brain, the PBR is enriched in glial
cells, astrocytes, and microglia, but it is also found in
some principal neurons. Although most actions of BZs
can be explained by facilitation of GABAA receptors
(see Table 2), it is possible that they also partly act via
stimulation of neurosteroid synthesis (progesterone = .
allopregnanolone; deoxycorticosterone = . 3a,5atetrahydrodeoxycorticosterone) as recently shown
for some brain mechanisms with a neurosteroid synthesis blocker finasteride abolishing the effects of BZs
(Rupprecht et al., 2009; Tokuda et al., 2010). Importantly,

these neurosteroids have rapid effects via allosteric

modulation of GABAA receptors. Novel TSPO ligands
have shown efficacy in reducing anxiety in animal
models and initial human experiments (Rupprecht
et al., 2010), in the absence of affinity to GABAA
receptors. TSPO ligands are being also developed as
PET ligands to monitor glial cell dynamics in vivo in the
brain, including microglial activation as a measure of
neuroinflammation (e.g., Van Camp et al., 2010).
2. Neuroplasticity Induced by Benzodiazepines and
Related Compounds. Sedative compounds like BZs
are generally known to depress brain activity, both in
animal models and humans (Kelly and McCulloch,
1982; Kelly et al., 1986; Wang et al., 1996; Freo et al.,
2008). Ito et al. (1994) compared clonazepam (that acts
selectively on BZ sites of the GABAA receptor, not on

TABLE 2
Summary of the roles of GABAA receptor subunits in benzodiazepine- and GABA-site drug effects and in neuroplasticity-related phenomena in
the brain
Subunit

a1

a2

Subtypesa

Location

a1bg2,

60%, syn and extrasyn

a1bd

all brain regions, incl.

interneurons

a2bg2

syn, limbic areas, cortex,

principal neurons

Behavior/Physiology

Model

References

BZ: sedation, anterograde amnesia,

anticonvulsant effect, addiction,
reward, anxiolysis?
- developmental plasticity
- depression of brain activity?
- conditioned fear
- neuroplasticity of VTA DA neurons

s.d.: zolpidem

(Low et al., 2000)

a1(His101Arg)

(Smith et al., 2012)

(Crestani et al., 2000)
(Tobler et al., 2001)
(Tan et al., 2010)
(Li et al., 2009)
(Huopaniemi et al., 2004)
(Fagiolini et al., 2004)
(Heikkinen et al., 2009)

BZ: anxiolysis, analgesia, anesthesia,

myorelaxation, addiction?
- adult neurogenesis
- CTA to ethanol
- conditioned fear
- reduction of ICSS threshold
(reward)

s.d.:

(Low et al., 2000)

a2(His101Arg)
a2-KO

(Crestani et al., 2001)

(Blednov et al., 2013)
(Smith et al., 2012)
(Reynolds et al., 2012)
(Witschi et al., 2011)
(Knabl et al., 2008)
(Duveau et al., 2011)

a3

a3bg2

syn and extrasyn, limbic

areas, monoamine
neurons, reticular
nucleus of thalamus,
principal neurons

BZ: myorelaxation, anesthesia,

analgesia, anxiolysis, addiction?
-thalamocortical oscillations,
regulated by endozepines?
- reduction of ICSS threshold
(reward)
- sensorimotor gating

s.d.: TP003

(Low et al., 2000)

a3(His126Arg)

(Crestani et al., 2001)

a3-KO

(Straub et al., 2013)

(Christian et al., 2013)
(Reynolds et al., 2012)
(Knabl et al., 2008)
(Yee et al., 2005)
(Sohal et al., 2003)

a5

a5bg2

extrasyn, hippocampus,
cortex, principal
neurons

BZ: learning and memory

-sensorimotor gating
-BZ tolerance

zolpidem-IS
s.d: L-655708
a5(His105Arg)
a5-KO

(Hauser et al., 2005)

(Yee et al., 2004)
(van Rijnsoever et al., 2004)
(Crestani et al., 2002)

a4, a6, d

a4/6bg2,

syn (g2), extrasyn (d),

cerebellum (a6),
forebrain (a4)

BZ-IS

s.d.: gaboxadol,
neurosteroids
a4-KO
a6-KO

(Duveau et al., 2011)

a4/6bd

sedation, sleep, anesthesia

- tonic inhibition
- depression of brain activity
- adult neurogenesis (a4)
- neuroplasticity of VTA DA neurons

(Vashchinkina et al., 2012, 2014a)

(Stell et al., 2003)
(Chandra et al., 2006)
(Jones et al., 1997)
(Brickley et al., 2001)

BZ, benzodiazepine; CTA, conditioned taste aversion; ICSS, intracranial self-stimulation; KO, knockout; IS, insensitive; s.d., selective drug; syn, synaptic; extrasyn,
extrasynaptic; VTA, ventral tegmental area.
a
Receptor subtypes are from the review of Olsen and Sieghart (2008).

Drug-Induced Neuroplasticity

TSPO) and the GABA-site agonist muscimol in rats

using [14C]deoxy-D-glucose autoradiography, and found
reductions of brain glucose uptake by both of them.
However, although clonazepam reduction plateaued at
30% reduction, the effect of muscimol was linearly
related to estimated receptor occupancy at least until
60% reduction of glucose uptake. These results suggest
a major difference in how ligands affecting preferentially synaptic and extrasynaptic GABAA receptors
influence brain metabolism. In addition, these results
generally agree with depressed neuronal activation
after treatments with GABAA agonist drugs using
immediate early gene assays, such as immunohistochemistry of c-Fos expression (see below).
Acute BZs generally depress also gene expression in
the brain (Huopaniemi et al., 2004), except for the CeA
(Beck and Fibiger, 1995; Hitzemann and Hitzemann,
1999; Shaw et al., 2011; Panhelainen and Korpi, 2012).
Induction of immediate early genes in the CeA is
common for various anxiolytics, but not specific for
them (Thompson and Rosen, 2006). Huopaniemi et al.
(2004) used a high dose of diazepam in mice (30 mg/kg)
and found a short reduction in expression of neuroplasticityrelated genes such as BDNF and c-Fos, but, interestingly,
the expression of CaMKIIa remained diminished for
at least 40 hours after a single diazepam administration. These effects on gene expression were not observed
in a1(His101Arg) knock-in mice. Thus, ligands promoting the activity of the main type of GABAA receptor
(a1 subunit-containing) depress brain activity and gene
expression, and by that they might not be expected to
induce neuroplasticity changes in the brain. Acute BZ
treatments might thus strongly prevent neuroplasticity.
In addition, Licata et al. (2013) found that single doses
of triazolam and zolpidem reduced BDNF in the mouse
HC, but unexpectedly a 7-day twice daily treatment with
diazepam or zolpidem failed to change BDNF expression.
However, concurrent 2- to 3-week diazepam treatment
prevents the stimulation of neurogenesis by fluoxetine in
normal rats (Wu and Castren, 2009) and in socially
isolated anxious rats (Sun et al., 2013). It remains to be
tested whether even a single administration of BZs would
prevent antidepressant-induced neuroplasticity in the
rat models.
Acute effects of BZs on DA release and synthesis have
been contradictory, not fully supporting any role for
midbrain DA neurons in reinforcing and dependenceproducing effects of BZs. However, Heikkinen et al.
(2009) observed similar increase in AMPAR/NMDAR
current ratios of VTA DA neurons ex vivo 13 days after
a single administration of diazepam and the GABAA
receptor a1 subunit-preferring zolpidem. This effect
could be blocked by the benzodiazepine-site antagonist
flumazenil and, interestingly, by the NMDAR antagonist dizocilpine. This finding was confirmed and extended by Tan et al. (2010) by showing that midazolam,
either systemically or intra-VTA, induced a persistent

937

change in DA neuron glutamate synapses. AMPARmediated responses showed inward rectification at

positive holding potential in the presence of intracellularly added polyamines, indicating increased targeting
of Ca2+-permeable non-GluA2 AMPA receptor subunits
(Jonas and Burnashev, 1995; Dingledine et al., 1999).
Furthermore, they showed that the primary target of
midazolam was the local GABAergic interneuron
expressing a1 subunit-containing GABAA receptors.
This result was confirmed by using a1(His101Arg)
mutant mice, indicating that the effect by BZs was
mediated by disinhibition of DA neurons. In proof, by
recording spontaneous IPSCs, Tan et al. (2010) observed that midazolam increased the phasic synaptic
inhibition of the VTA GABA neurons, whereas at the
same time the synaptic inhibition of the DA neurons
was diminished. Furthermore, in a1(His101Arg) mouse
midbrain slices, midazolam was ineffective in inhibiting
GABA neurons, which was now accompanied with
greater inhibitory current in DA neurons.
These recent findings clearly indicate that BZ addiction may also have a similar positive reinforcing
component as most other drugs of abuse (e.g., see Ator
et al., 2005; Straub et al., 2010). This component adds to
the better-known negative reinforcement, such as BZinduced relief from punishment or from anxious dysphoria, guilt, and shame. It is also plausible that BZs
have more widespread neuroplasticity effects in other
brain regions such as the HC (for chronic BZ withdrawal
effects, see Shen et al., 2009), although the persistency
and efficacy of single versus chronic dosing are still
poorly known. However, it should be kept in mind that
BZ agonists are especially efficient in reducing conflict
arising from internal or external cues in simple and
more complicated experimental animal tests, such as
Vogel and Geller-Seifter conflict tests (Nazar et al.,
1997; Millan and Brocco, 2003), and conditioned
taste aversion and neophobia tests (Yasoshima and
Yamamoto, 2005; Wislowska-Stanek et al., 2008;
Callaerts-Vegh et al., 2009). Furthermore, the BZ
lorazepam can reverse punishment-suppressed operant
responding for the opioid remifentanil in rats (Panlilio
et al., 2005), indicating its efficacy in reversing the
aversion-induced change in behavior (a conflict situation,
punishment by mild footshocks). However, it was inefficient in reinstating extinguished responding for remifentanil, whereas heroin was effective in both reversing
punishment-suppressed and extinguished responding.
Thus, BZs are efficient in counteracting learned aversion-induced behaviors, by negative reinforcement, and in
addition to their direct reinforcing effect. Most likely,
other related anxiolytic GABAA agonists and other drugs
showing efficacy in conflict situations (Millan and Brocco,
2003) would reinstate punishment-suppressed responding. Whether this effect is a long-lasting one is not known.
Anyway, the possibility that an abstinent alcoholic or
a drug addict might lose the abstinence-promoting effect

938

Korpi et al.

of social control/punishment should be taken into account

when prescribing anxiolytic drugs. One interesting example of the short-term BZ effect is the midazolam-induced
attenuation of conditioned (LiCl, i.p.) taste aversion to
sucrose, which unfortunately returned back to full aversion in the next session (Yasoshima and Yamamoto,
2005).
Does the acute stimulation of tonic extrasynaptic
GABAergic inhibition by selective drugs induce neuroplasticity in VTA DA neurons? This question was studied
by Vashchinkina et al. (2012, 2014a). First, the GABAsite agonist gaboxadol (4,5,6,7-tetrahydroisoxazolo(5,4-c)
pyridin-3-ol), which is a superagonist at d subunitcontaining receptors, whereas GABA is a partial agonist
(Storustovu and Ebert, 2006; Saarelainen et al., 2008),
induced prolonged (.6 days) increase in AMPAR/
NMDAR current ratios and AMPAR current rectification
in VTA DA neurons 24144 hours after a single sedative
dose in a dose-dependent manner (Vashchinkina et al.,
2012). Second, this finding was extended to a neurosteroid
agonist ganaxolone, which does not have genomic effects
like endogenous neurosteroids (Carter et al., 1997). A
single mildly sedative dose of ganaxolone induced a similar long-lasting neuroplasticity in VTA DA neurons ex
vivo as a dose of gaboxadol (Vashchinkina et al., 2014a).
By using a GAD67-GFP knock-in mouse line, in which
GABA neurons are fluorescently labeled, ganaxolone in
vitro provoked a fourfold increase in tonic GABAAmediated conductance in VTA GABA neurons, but not
in DA neurons of the TH-EFGP transgenic mice. In vitro
incubation of midbrain slices with 0.5 mM ganaxolone for
.4 hours also induced increased AMPAR/NMDAR current ratio in DA neurons. In agreement with the preference for d subunit-containing receptors, the
neuroplasticity effects of gaboxadol and ganaxolone were
abolished in d-KO mice (Vashchinkina et al., 2012,
2014a). However, the level of d subunit protein expression
in VTA GABA neurons is not very high, at least compared
with the cerebellar granule neurons, and, therefore,
direct immunohistochemical demonstration of its presence has failed because of background labeling even in the
d-KO mice by available d subunit antibodies (unpublished).These results indicate that drugs potentiating
tonic inhibitory conductance also target primarily
GABAergic interneurons in the VTA and induce neuroplasticity effects in DA neurons by disinhibition.
Surprisingly, both gaboxadol and ganaxolone failed to
induce CPP, and if anything they induced aversion
(Vashchinkina et al., 2012, 2014a). Gaboxadol failed to
sustain the acute nose-poking response in mice using
the yoked control paradigm of intravenous administration over a wide dose range nor was it self-administered
in cocaine-primed baboons, although the BZ agonist
triazolam could replace cocaine (Vashchinkina et al.,
2012). In line with the electrophysiological results,
conditioned aversion to ganaxolone was abolished in
d-KO mice (Vashchinkina et al., 2014a). Because a short

aversive swimming stress induces neuroplasticity in

VTA DA neurons (Saal et al., 2003), it appears possible
that there are several populations of midbrain (and
VTA) DA neurons that may be similarly/differentially
adapted to various rewarding and aversive stimuli
(Matsumoto and Hikosaka, 2009; Bromberg-Martin
et al., 2010; Lammel et al., 2011, 2012; Fiorillo, 2013;
Fiorillo et al., 2013; Jennings et al., 2013; Ilango et al.,
2014). It is also possible that triggering conditioned
aversion takes place primarily in other brain regions,
such as the BNST (Kim et al., 2013b) and/or the LHb
(Matsumoto and Hikosaka, 2007; Hikosaka, 2010;
Stamatakis and Stuber, 2012), which have reciprocal
connections with the VTA.
Ca2+-permeable NMDARs are often involved in LTP,
but in NMDAR-independent forms of LTP, VGCC are
important (Morgan and Teyler, 1999; Bauer et al., 2002;
Schroeder and Shinnick-Gallagher, 2004; Bloodgood
and Sabatini, 2007). Tietz et al. (see below for references) made a series of detailed experiments on the
mechanisms of tolerance to and withdrawal from subchronic flurazepam treatment in the hippocampal CA1
area. They treated rats with a high oral dose of
flurazepam for at least 1 week and studied the brains
under tolerant and 12 day withdrawal conditions.
Several interesting transient changes were observed
in their studies. Downregulation of GABAA receptorassociated ligand binding and GABAA receptor subunit
levels took place in several brain regions of tolerant
animals (Rosenberg et al., 1985; Tietz et al., 1999) (for
a review on GABAA subunit expression after various
GABAA drugs, see Uusi-Oukari and Korpi, 2010).
Surprisingly, the changes in the GABAA system and
tolerant behavior were abolished in the tolerant, withdrawal BZ-free state by a single administration of the
BZ antagonist flumazenil (Tietz et al., 1999), with
the testing being carried out 1 day after the injection
of the short-acting flumazenil. Increased AMPAR currents and binding sites were detected in the hippocampal CA1 and CA3, but not dentate gyrus, region of
withdrawing animals (Van Sickle and Tietz, 2002), the
increased currents correlating with increased withdrawal anxiety (Xiang and Tietz, 2007; Xiang et al.,
2008). GluA1, but not GluA2, subunit protein was
increased synaptically (Das et al., 2008) because of
GluA1 subunit phosphorylation at Ser831 by CaMKII
(Earl et al., 2012). Whereas the increase in AMPAR
function could not be abolished by the NMDAR antagonist dizocipline (MK-801), it was abolished by the
L-type VGCC blocker nimodipine, which also reversed
withdrawal anxiety. At day 2 of withdrawal, the levels
of GluN1 and GluN2B subunits and NMDAR function
were also downregulated, which could be reversed by
blocking AMPARs and their upregulation (Van Sickle
et al., 2004; Xiang and Tietz, 2007), suggesting that the
change in AMPAR was the primary alteration in the
glutamate system in BZ tolerance. These results

Drug-Induced Neuroplasticity

demonstrate an important cascade of transient (14

days) functionally interrelated changes in the hippocampal neurons that are caused by chronic, but not
acute (Van Sickle et al., 2002), BZ administration.
These results suggest that even chronic heavy BZ
treatment induces rather short-lasting effects at least
on behavior and HC, but that they also show some
potential for inducing neuroplasticity.
3. Behavioral After-effects of g-Aminobutyric Acid A
Drugs. Once the single-dose neuroplasticity effect of
the BZ agonists was found (Heikkinen et al., 2009; Tan
et al., 2010), it was of interest to study whether behavioral responses to other drugs of abuse would be affected
by pretreatment (and neuroplasticity effects) of BZs.
Panhelainen et al. (2011) gave a single injection of
diazepam (5 mg/kg i.p.) and tested adolescent and adult
mice for psychomotor stimulation by three daily doses of
morphine and d-AMPH. In contrast to a hypothesis of
enhanced psychomotor activation, based on the sensitizing effects of viral-mediated upregulation of GluA1
subunit in the midbrain (Carlezon and Nestler, 2002),
we found that diazepam pretreatment reduced locomotor responses to morphine (in both sexes) and attenuated behavioral locomotor sensitization to d-AMPH,
with the effects being detectable, although slightly
diminished, also in adult mice (Panhelainen et al.,
2011). The effects on d-AMPH-induced sensitization
could be blocked by a single injection of dizocilpine prior
to diazepam pretreatment. These preliminary results
suggest that occlusion of neuroplasticity attenuates
behavioral effects induced by acute and repeated morphine and amphetamine.
Because gaboxadol also induces neuroplasticity in VTA
DA neurons, which lasted even longer that that induced
by diazepam (Vashchinkina et al., 2012), we repeated
Panhelainens study (Panhelainen et al., 2011) to test
whether the pretreatment with gaboxadol would also affect
the psychomotor stimulation by morphine and d-AMPH.
However, we observed no alterations in the responses in
adolescent or adult mice (unpublished results). This
suggested that rewarding BZs and aversive gaboxadol
might induce neuroplasticity in different populations of
VTA DA neurons, but preliminary examination did not
indicate any regional variation in the VTA of DA neurons
with altered glutamate transmission after gaboxadol
(Vashchinkina et al., 2012). It is also possible that GABAA
receptor drugs persistently affect many brain regions
other than the VTA. To start examining this possibility, we counted c-Fos positive neurons in aversionassociated brain regions 2 hours after a single injection
(6 mg/kg) of gaboxadol (when sedation was gone), and,
interestingly, found a significant activation exclusively
in the oval part of the BNST (E. Vashchinkina et al.,
submitted manuscript). In parallel behavioral tests,
gaboxadol provoked a mild anxiety-like withdrawal
state, which was preceded by transiently increased
plasma corticosterone level.

939

In addition, we examined whether selective blockade

of CRF1 receptors would attenuate gaboxadol-induced
plasticity in VTA DA neurons, because CRF signaling is
often involved in oval BNST-mediated behaviors (Erb
et al., 2001b; Beckerman et al., 2013). Indeed, gaboxadolinduced VTA DA neuron plasticity was totally blocked by
pretreatment with CP-154526, a selective CRF1 receptor
antagonist (Shaham et al., 1998) (E. Vashchinkina et al.,
submitted manuscript). Thus, VTA DA plasticity and
anxiogenic/aversive consequences of activation of extrasynaptic GABAA receptors seem to be linked to activation
of oval BNST and CRF1 signaling.
In contrast to gaboxadol experiments, 2 hours after
diazepam administration, a strong increase in the
number of c-Fos-positive cells was found in the CeA
(Panhelainen and Korpi, 2012). In addition, by using the
Golgi method for counting dendritic spines, we found
that a single dose of gaboxadol increased spine counts in
the HC, whereas diazepam was inactive (Vashchinkina
et al., 2014b). These results suggest that the effects on
brain-wide cellular activity are different in diazepamand gaboxadol-treated mice, making it possible that
synaptic and extrasynaptic GABAA neurotransmissions
modulate different pathways to the VTA DA neurons.
4. Effects of Flumazenil on Benzodiazepine and
Alcohol Tolerance. Flumazenil (Hunkeler et al., 1981)
is acutely very efficient and specific in clinically antagonizing the actions of all BZ-site agonists, whether they
have the BZ structure or other chemical structures, such
as zolpidem and zopiclone. It is available as intravenous
injection and its half-life is short (about 1 hour) in humans
(Klotz et al., 1984; Roncari et al., 1993). It is primarily
used in BZ intoxications or in the treatment and diagnosis
of drug intoxications (Hoffman and Warren, 1993;
Kreshak et al., 2012). As a competitive BZ antagonist,
its acute actions can be well understood as counteracting
the effects of agonists.
Interestingly, flumazenil has shown variable intrinsic activity in preclinical and clinical settings, varying
from weak partial agonism (positive allosteric modulation) to partial inverse agonism (negative modulation)
(e.g., File et al., 1982a,b; Nutt et al., 1990; Da Cunha
et al., 1992; Smolnik et al., 1998; Izumi et al., 1999;
Goulenok et al., 2002). Its intrinsic efficacy has been
explained by antagonism of endogenous positive or
negative modulators. Indeed, there is evidence for
endogenous production of compounds with binding
and functional activity at BZ sites (endozepines), such
as diazepam and its metabolite desmethyldiazepam
(Sangameswaran et al., 1986; Klotz, 1991), and molecules with other structures, including heme derivates
(Ruscito and Harrison, 2003) and the diazepam binding
inhibitor (DBI) and its proteolytic peptide fragments,
such as octadecaneuropeptide (Alho et al., 1985; Costa
and Guidotti, 1991). Recently, DBI and octadecaneuropeptide have been shown to increase neurogenesis in
postnatal mouse subventricular zone by negative

940

Korpi et al.

modulation of GABAA receptors (Alfonso et al., 2012),

and, surprisingly, DBI was described to positively
modulate reticular thalamic a3 subunit-containing
GABAA receptors, an effect that appears to be needed
for antiabsence seizure effect in a mouse model
(Christian et al., 2013). Production of endozepines is
especially high during acute hepatic failure with and
without encephalopathy (Olasmaa et al., 1990; Avallone
et al., 1998). This state is also associated with increased
levels, expression, and function of the DBI peptide and
TSPO protein, which also leads to increased levels of
neurosteroids THDOC and allopregnanolone (Rothstein
et al., 1989; Itzhak et al., 1995; Ahboucha et al., 2006,
2012). Flumazenil has a therapeutic effect in patients
with hepatic encephalopathy and coma (Bansky et al.,
1989; Goulenok et al., 2002), although it does not
counteract the effects of neurosteroids. Although the
setpoint of the GABAA receptors determining positive or
negative BZ modulation might be different between
different subjects or it might change because of illness
or drug treatment, it is possible that at least a part of
the intrinsic activity of flumazenil can be accounted for
by antagonism of various endogenous ligands.
In regard to the present review, a most interesting
finding has been the efficacy of flumazenil to reverse BZ
and alcohol tolerance and dependence in preclinical
models by a single dose or by a pretreatment (Buck
et al., 1991; Flaishon et al., 2003; but see Nutt and
Costello, 1988; Loscher and Rundfeldt, 1990; Tietz
et al., 1999). Although this phenomenon has been tested
in BZ-dependent patients with inconsistent efficacy for
counteracting tolerance in acute settings (Cittadini and
Lader, 1991; Savic et al., 1991; Lader and Morton,
1992), a small clinical study has reported preliminary
results on prolonged subcutaneous flumazenil administration in withdrawing BZ-dependent patients (Hulse
et al., 2013), suggesting that perhaps longer treatments
are needed in human populations. Another study using
twice daily intravenous injections of flumazenil showed
that flumazenil significantly blocked withdrawal symptoms and kept the patients better in abstinence (Gerra
et al., 2002). Because flumazenil increases membrane
targeting of GABAA receptors (Flaishon et al., 2003;
Pericic et al., 2004), its efficacy in reversing BZ tolerance and in alleviating withdrawal in dependent subjects may at least partly be based on increased number
of functional GABAA receptors.
5. Treatment of Addictions by g-Aminobutyric Acid B
Receptor Agonists. Although the ligand-gated anion
channel GABAA receptors mediate fast phasic inhibition
and prolonged tonic inhibition in the mature nervous
system, the GPCR metabotropic GABAB receptors mediate neuronal inhibition by slower actions on neuronal
metabolism and K+ and Ca2+ channels both presynaptically at inhibitory and excitatory terminals and postsynaptically on dendrites and spines (Bowery et al., 2002;
Bettler et al., 2004). GABAB receptors are heterodimers of

two subunits, GABAB1 and GABAB2, that are large

(110 kDa) proteins with seven transmembrane domains
and long extracellular N terminus. GABAB1 seems to be
responsible for GABA binding and GABAB2 in turn for
G protein coupling (Bettler et al., 2004). Knockout of
either subunit eliminates the typical GABAB receptor
responses (Schuler et al., 2001; Gassmann et al., 2004). In
the simplest case, activation of presynaptic GABAB autoand heteroreceptors inhibits, via released Gi/o protein bg
subunits, the P/Q-type (Cav2.1) and N-type (Cav2.2)
currents of high VGCC. Stimulation of postsynaptic
GABAB receptors activates in the same way multiple
types of K+ channels, including inwardly rectifying Kir3
channels. After both presynaptic and postsynaptic activation, there is the release of Gi/oa subunits that inhibits
AC, leading to reduced cAMP production and PKA
activity (Bettler et al., 2004; Koyrakh et al., 2005). The
signaling of GABAB receptors is most likely more complicated and neuronal cell-population specific because of
differences in the receptors cell surface expression and
localization (Becher et al., 2004), isoform diversity (Bettler
et al., 2004), crosstalk with various ionotropic (e.g., GABAA,
NMDA), and metabotropic (e.g., mGlu, TrkB) receptors
(reviewed in Xu et al., 2014) and GABAB receptor interacting proteins. Notably, GABAB receptors interact with
several other proteins, including activating transcription
factor 4, inducing a novel signaling pathway (Nehring et al.,
2000; Vernon et al., 2001; Chen et al., 2003), regulators of G
protein signaling (RGS) (Labouebe et al., 2007), and, most
recently, potassium channel tetramerization domaincontaining proteins that bind to the intracellular carboxy
terminus and alter agonist sensitivity and desensitization
(Schwenk et al., 2010). In relation to neuroplasticity, it is
important to note that GABAB receptor activation reduces
the Ca2+ flux via NMDARs both by producing hyperpolarization due to opening of K+ channels and/or by reducing
the activities of AC and PKA, which reduces the phosphorylation of NMDAR subunits (Morrisett et al., 1991;
Chalifoux and Carter, 2010).
Activation of GABAB receptors inhibits the spontaneous pacemaker-like firing of VTA DA neurons ex vivo
(Seutin et al., 1994; Wu et al., 1999) and attenuates the
firing rate and burst firing of these neurons in vivo
(Erhardt et al., 2002). Therefore, facilitation of the GABA
system is being tested for the treatment of various drug
addictions, with two main lines of approach. Stimulation
of GABAB receptors reduces rewarding effects and
consumption of several addictive drugs in various preclinical models (Roberts, 2005; Vlachou and Markou,
2010), but so far the results from the treatment trials
on human addictions, especially on alcoholism, with the
selective direct sedative agonist baclofen [(3R)-4-amino-3(4-chlorophenyl)butanoic acid] have been inconsistent
(Tyacke et al., 2010; Agabio et al., 2013; Brennan et al.,
2013; Agabio and Colombo, 2014). To date, baclofen is the
only GABAB receptor agonist approved in clinical use, in
addition to g-hydroxybutyrate (see below).

Drug-Induced Neuroplasticity

The research focus is now on positive allosteric

modulators that act on a GABAB receptor site distinct
from GABA and baclofen (Pin and Prezeau, 2007).
Because positive allosteric modulators facilitate the
effects of GABA-site ligands (Jensen and Spalding,
2004), they alter activated receptors only. Hence they
rather enhance the physiologic pattern of GABAB receptor activation, and so may have less adverse effects
than ligands that alter all GABAB receptors. In agreement, allosteric modulators interfere less with locomotor activity (Ong and Kerr, 2005) and do not induce
hypothermia (Jacobson and Cryan, 2008).
It is not known whether the activation of GABAB
receptors would persistently reverse any addictionrelated neuroplasticity. Importantly, these drugs have
not shown any rewarding potential in intracranial selfstimulation or CPP paradigms, although they attenuate
addiction-related behavior such as sensitization, druginduced CPP, and SA of various addictive substances
(for review and references, see Filip et al., 2015).
Furthermore, there are features in GABAB receptor
activation that indicate reduction of neuroplasticity in
adult animals. These are inhibition of neurogenesis
(Giachino et al., 2014), increased expression of activating transcription factor 4 that reduces brain gene
expression and neuroplasticity (Nehring et al., 2000;
Vernon et al., 2001; Chen et al., 2003), reduced expression of BDNF (GABAB antagonists and receptor subunit
knockouts increase BDNF (Heese et al., 2000; Enna
et al., 2006) and, importantly, PKA-mediated blunting
of NMDAR-dependent Ca2+-transients of dendritic
spines in the PFC layer 2/3 (Chalifoux and Carter,
2010). In addition, GABAB receptors retard the synaptic
vesicle priming in glutamate synapses by reducing
cAMP (Sakaba and Neher, 2003). It is still unclear
whether activation or inhibition of GABAB receptors is
antidepressant (Cryan and Slattery, 2010), which may
turn out to be a complicating factor in the therapeutic
use of GABAB ligands.
Another interesting alternative for antiaddiction
drug treatment might be the antiepileptic, irreversible
GABA transaminase (GABA-T) blocker g-vinyl-GABA,
vigabatrin, which increases brain and cerebrospinal
fluid GABA concentration (Halonen et al., 1988; Petroff
et al., 1996). Vigabatrin reduces neurochemical changes
produced by cocaine in the brain reward areas, including
cocaine-induced DA release and cocaine consumption in
preclinical models (Dewey et al., 1997; Kushner et al.,
1997, 1999; Peng et al., 2008). At least some of its actions
can be abolished by GABAB receptor antagonists (Ashby
et al., 1999). Vigabatrin also affects synaptic and
extrasynaptic GABAA transmission (Overstreet and
Westbrook, 2001). Importantly, vigabatrin and a reversible GABA-T blocker ACC (1R,4S-4-amino-cyclopent-2ene-carboxylic acid) do not induce CPP (Paul et al., 2001;
Ashby et al., 2002). Vigabatrin has shown neuroprotective effects in epilepsy models (Halonen et al., 1995;

941

Pitkanen et al., 1996). Initial experiments showed some

efficacy in human cocaine addicts (Brodie et al., 2009), but
a larger study failed to show significant effects, perhaps
due to poor adherence of the addicts to vigabatrin
treatment (Somoza et al., 2013). This drug was originally
developed for epilepsy, in which indication it was efficient,
but permanent, slowly progressing vigabatrin-associated
visual field loss, possibly linked to its cumulative dosing,
has limited its use in epilepsy (Malmgren et al., 2001;
Maguire et al., 2010; Clayton et al., 2013). The mechanism
of retinal damage is not known (Ravindran et al., 2001). All
these efforts have led to the development of a more potent
GABA-T blocker, (1S, 3S)-3-amino-4-difluoromethylenyl1-cyclopentanoic acid (CPP-115) (Pan et al., 2012), which is
being further studied. As with GABAB agonists, there is no
clear information on possible long-term reversal of
addiction-related neuroplasticity by GABA-T blockers.
6. g-Hydroxybutyrate as a Drug of Abuse and
a Therapeutic Compound. GHB was originally synthesized for sedation and anesthesia, and as a GABA
analog it was supposed to enter the brain and act on
GABA receptors easier than exogenous GABA (Laborit,
1964). This short-chain fatty acid compound [half-life in
plasma about 1 hour (Abanades et al., 2006)] was used
for anesthesia (Kam and Yoong, 1998), but now it is
mainly used, with the non-proprietary name sodium
oxybate, in narcolepsy with cataplexy. It improves
consolidation of nonrapid eye movement sleep and
normalizes sleep stage shifts, and through these mechanisms particularly reduces appearance of daytime
cataplexic attacks in narcolepsy patients (Mamelak,
2009; Boscolo-Berto et al., 2012). It is also used in some
European countries in the treatment of alcohol withdrawal symptoms and in the maintenance of alcohol
abstinence (Leone et al., 2010). Interestingly, when
used at low doses in the treatment of narcolepsy, very
little tolerance develops to its sleep-improving effects,
but when abused for its euphoric and intoxicating
effects at high doses, tolerance and dependence develops and withdrawal symptoms appear spontaneously
(or in nonhuman primates after administration of
GABAB receptor antagonists) (Goodwin et al., 2013).
GHB is an endogenous compound, synthesized from
GABA and found in the brain at about 1 mM concentration (Maitre, 1997), but when exogenously given in
preclinical settings for sedative and hypothermic effects,
the doses needed are so high that brain concentrations
are elevated up to 1 mM (Klein et al., 2009), which are in
agreement with EC50 of about 1 mM to activate GABAB
receptors in midbrain slices (Madden and Johnson, 1998).
The preclinical effects of high GHB doses are dependent
on GABAB receptor activation (Kaupmann et al., 2003).
The identity (and significance) of the high-affinity GHB
binding site(s) in the brain is not known. These sites
might represent specific GHB receptor, unaffected in
GABAB knockout mice (Kaupmann et al., 2003), and/or
partly reflect the most sensitive GABAA receptors, the

942

Korpi et al.

extrasynaptic a4b1d receptors (Absalom et al., 2012).

However, these highly GHB-sensitive GABAA receptors
could not be found in specific thalamic, NAc, or HC
dentate gyrus neurons with known tonic inhibitory
currents examined with electrophysiological patchclamp methods in the brain slices from juvenile rats
(Connelly et al., 2013).
GHB has variable effects on firing of midbrain DA
neurons; both inhibition and activation of VTA DA have
been produced in animal models (Pistis et al., 2005).
Interestingly, RGS2 protein has been suggested to be
responsible for the high and low efficacy coupling of the
GABAB receptors to somatodendritic Kir3 K+ channels
in the VTA GABA and DA neurons, respectively
(Labouebe et al., 2007), which seems to explain why
GHB can acutely inhibit the GABA neurons similarly to
baclofen (Cruz et al., 2004). But, when GHB was given
subchronically at a high dose, animals showed aversion
to consuming the initially preferred GHB-containing
sucrose solution. This change coincided with the reduction of RGS2 expression in the VTA DA neurons and
the enhanced inhibition of these neurons by GABAB
activation (Labouebe et al., 2007). Recent experiments
on the effects of acute GHB on brain gene expression
have further indicated that GHB induces neuroplasticity changes in the brain (van Amsterdam et al., 2012).
This is consistent with the development of tolerance
and rewarding effects to repeated GHB administration
(Itzhak and Ali, 2002). Similarly to sedative GABAA
agonists, GHB globally reduces rat brain glucose metabolism (Kuschinsky et al., 1985). However, GHB provoked
surprisingly robust activation of c-Fos protein in many
subcortical brain areas, shared by similar effects by an
equipotent sedative dose of baclofen (van Nieuwenhuijzen
et al., 2009). The activation of thalamic nuclei, including
the LHb in the epithalamus, after high GHB doses that
induce cortical spiking (modeling absence seizures) can
be explained by the oscillating thalamocortical circuits
(Zhang et al., 1991; van Nieuwenhuijzen et al., 2009).
Importantly, the some of the reward-related areas, such
as the VTA and NAc, were clearly not activated by GHB
or baclofen (van Nieuwenhuijzen et al., 2009). Thus,
GHB remains an interesting, although a difficult compound in relation to addictions, with still much to be
learned about basic neurobiology and mechanisms of
action that contribute to its endogenous physiologic
functions, to mechanisms of abuse of exogenous GHB
and to its use in the treatment of alcohol addiction.
Finally, it should be remembered that GHB has similar
abuse liability to sedative drugs and alcohol (Griffiths
and Johnson, 2005; Carter et al., 2006; Johnson and
Griffiths, 2013), with severe delirium presenting in
many cases where use has been extensive and tolerance
has developed. This withdrawal state is hard to treat
with BZs, and GHB may need to be reinstigated and
then tapered slowly (de Jong et al., 2012). Baclofen
might be useful here, too.

7. Anesthetics and Neuroplasticity. Several inhalational (isoflurane, halothane, and sevoflurane) and intravenous (propofol, etomidate, barbiturates, and BZs)
anesthetics facilitate the function of GABAA receptors,
most likely as a part of their clinical mechanisms of
action (Sonner et al., 2003; Franks and Lieb, 2004;
Rudolph and Antkowiak, 2004). In addition to BZs and
barbiturates, these drugs might have addiction potential, but this question has not been much studied.
Propofol abuse has been reported (Wilson et al., 2010;
Bonnet and Scherbaum, 2012). In a recent study,
propofol showed abuse liability and euphoria on the
first exposure in patients undergoing sedation for
endoscopic examination (Kim et al., 2013a).
Because GABAA receptors are, at least in early brain
development, excitatory and essential for the normal
development of neuronal circuits (Akerman and Cline,
2007; Ben-Ari et al., 2007), prolonged facilitation or
activation of these receptor channels may have strong
effects on brain structure and function. Similarly, the
blockade of the NMDARs with ketamine, phencyclidine,
and alcohol affects the developing nervous system
(Olney et al., 1991; Ikonomidou et al., 1999, 2000).
Early studies with chronic halothane administration
(10 ppm halothane/air, 8 hours/day, 5 days/week,
throughout development or in adulthood for about 1.5
months) showed in rats that structural changes evaluated with the Golgi method (retarded synaptogenesis,
impaired dendritic branching, and disruption of organelle structure) were more abundant in the young than
adult rodent nervous system (Quimby et al., 1974; Levin
et al., 1991), the changes generally correlating with
impaired results in tests for cognitive function. On the
other hand, the persistent effects of anesthetics on the
nervous system have recently been studied using prolonged (46 hours) anesthesia at the age when brain
development is still occurring. At that stage, many
clinically used anesthetics and also other neuropsychiatric
drugs such as antiepileptics seem to induce neurotoxicity
(apoptosis) in rodents and nonhuman primates (Vutskits
et al., 2006; Briner et al., 2010, 2011; Creeley and Olney,
2010; 2013; Brambrink et al., 2012a,b; Creeley et al., 2013;
Jevtovic-Todorovic et al., 2013), with often a single administration being neurotoxic. Prolonged pediatric anesthesias for more than 4 hours, which are presently
clinically justified and often unavoidable to provide the
best treatment of the pediatric patient, have putatively
been associated with cognitive impairment later in life
(Jevtovic-Todorovic et al., 2013). Therefore, because
proper anesthesia is important in surgical treatment,
future efforts should be aimed at shortening durations of
anesthesia, finding novel mechanisms of action for anesthetics that would not so globally involve the ligand-gated
receptors of the main neurotransmitter systems, and/or
finding pretreatment options that would limit the
neurotoxicity. For example, lithium and clonidine
might be two compounds with some efficacy to prevent

Drug-Induced Neuroplasticity

anesthetic-induced toxicity (Young et al., 2008; Straiko

et al., 2009; Ponten et al., 2012), whereas hypothermia
may be an option to protect the brain from ischemia/
excitotoxicity and effects of prolonged anesthetics
(Ikonomidou et al., 1989). Ketamine-induced apoptosis is
enhanced by cotreatment with diazepam or midazolam
in a rodent model (Fredriksson et al., 2004; Young et al.,
2005), but diazepam has still been long used to alleviate
psychotomimetic adverse effects of ketamine in humans.
In addition, magnesium loading that has been used in
(pre)eclampsia, may be neurotoxic for the developing
nervous system (Dribben et al., 2009), and at least one
clinical trial with MgSO4 supplementation to pregnant
women with preterm labor had to be preliminarily
stopped due to increased pediatric mortality (Mittendorf
et al., 1997), especially to neonatal intraventricular
hemorrhage (Mittendorf et al., 2002). These last cases
are just two examples of problems recently encountered
in the treatment affecting negatively the developing fetal
or neonatal brain.
In the VTA DA neurons of juvenile mice, a single
sedating dose of diazepam or midazolam induces persistent increases in AMPAR/NMDAR current ratios
(Heikkinen et al., 2009; Tan et al., 2010). Intravenous
anesthetic propofol in vitro at low micromolar concentrations activates AMPARs on VTA DA neurons (Li
et al., 2008). Interestingly, isoflurane anesthesia alone
has been tested in treatment-refractory depressed
patients and found to produce long-lasting antidepressant effect, which was similar to electroconvulsive
therapy (under isoflurane anesthesia) (Langer et al.,
1985, 1995). These results were recently confirmed in
a study on refractory depression, which also showed
that electroconvulsive therapy (on an average ten
15-minute sessions within 3 weeks) had modestly more
efficient antidepressant effect than isoflurane anesthesia alone at 4-week follow up, but produced more severe
neurocognitive adverse effects (Weeks et al., 2013). In
rats, 7 days after a single 2-hour isoflurane anesthesia,
avoidance learning and HC LTP at CA1 synapses were
impaired (Uchimoto et al., 2014). However, a similar
single anesthesia in mice induced only some deficits in
attention tests 1 week afterward, and most results of
an extensive battery of behavioral and physiologic
tests were not altered (Yonezaki et al., 2015). In any
case, further research on possible prolonged neuroplasticity effects of GABAAergic compounds appears
warranted.
8. Conclusions. Although the GABAergic system is
important for neuronal development and circuit functions in the mature nervous system, drugs like benzodiazepines that facilitate the actions of the GABAA
receptors have many effects on the nervous system that
limit neuroplasticity. This may be due to their strong
sedative effect. However, these drugs act by negative
reinforcement, and more recently, benzodiazepines
have been shown to induce similar glutamate synapse

943

neuroplasticity in the DA neurons of the reward system

as stimulants, opioids, and alcohol, suggesting also
potential for positive reinforcement. Prolonged use of
these drugs even in normal therapy may cause cognitive
impairment that may not be fully reversible. Because
GABAA receptors exist in multiple heterogeneous subtypes, subtype-selective BZ ligands have been studied,
but this work has not yet translated into less addictive
drugs. Initial studies on activation of extrasynaptic
GABAA receptors suggest that they might show aversive features, perhaps by inducing glutamate neuroplasticity in a stress/aversion-sensitive subpopulation
of DA neurons and/or by activating other stress/
aversion-related brain areas. GABAB receptors hold
promise as a target for novel addiction therapies with
specific positive allosteric modulators or via increased
GABA levels.
F. N-methyl-D-aspartate Receptor Antagonists
NMDA antagonists are also known as dissociatives or
dissociative hallucinogens because of their subjective
effects. These are described as feelings of sensory detachment or dissociation from the outside world coupled
with perceptual disturbances as well as catatonia-like
motor phenomena. They are clearly distinct from the overt
visual hallucinations produced by serotonin-type hallucinogens (Gouzoulis-Mayfrank et al., 2005; Muetzelfeldt
et al., 2008). The most commonly used dissociatives are
ketamine and phencyclidine (PCP), whereas a third
NMDAR antagonist known as MK-801 or dizocilpine
has been widely used in pharmacological research but
never gained popularity among recreational users. In
recent years there has also been an increase in the use of
structural analogs with similar pharmacological activity
in the so-called legal highs scene (Morris and Wallach,
2014; NIDA, 2015).
As NMDAR antagonists, primarily ketamine, are also
widely used medically, their effects on the nervous
system have been studied extensively, yet they remain
enigmatic because of their widely differing and dosedependent effects. PCP is known to produce psychotomimetic effects in humans and it was first proposed to
be a candidate for a model of drug-induced schizophrenia in the late 1950s (Domino and Luby, 2012; Luby
et al., 1959). This finding later opened the idea of
glutamatergic model of schizophrenia in the past two
decades (Javitt and Zukin, 1991; Javitt et al., 2012).
NMDAR antagonists have neuroprotective effects, but
they also have proven neurotoxic effects in rodents,
although their effects on nonhuman primates and
humans are still unclear (Low and Roland, 2004;
Shirakawa et al., 2013; Wang et al., 2013a). Much effort
has been put in to identify the putative mechanisms of
NMDAR antagonist-induced neuroplasticity (Olney
et al., 1989). What follows is a review of ketamine,
PCP, and MK-801 and their effects on neurogenesis,
neurotoxicity, and behavior.

944

Korpi et al.

1. Ketamine: a Dissociative Anesthetic with Rapid

Antidepressant Effects in Patients. Ketamine is a noncompetitive NMDAR antagonist and a dissociative anesthetic developed in 1962 (Jansen, 2000). Recently, it
has received a lot of attention for its rapid-onset antidepressant effects (Krystal et al., 2013). After the first
report on the surprisingly rapid antidepressant effect
after intravenous infusion of ketamine in depressed
patients (Berman et al., 2000), many reports reproduced
the results and demonstrated that the antidepressant
effects after a single dose (intravenous or intramuscular)
is sustained for 3 to 10 days (Diazgranados et al., 2010;
Zarate et al., 2012b; Chilukuri et al., 2014). Also repeated
infusions of ketamine produced long-term effects (aan het
Rot et al., 2010; Murrough et al., 2013; Diamond et al.,
2014). Because of these data, there is a strong interest to
understand the mechanisms of action of ketamine.
With regards to the neurochemical effects underlying
the antidepressive effects of ketamine, chronic ketamine
intake is associated with increases in serum BDNF in
humans (Ricci et al., 2011). Although one report in adult
rats and mice claimed that ketamine showed a transient
effect (at 50 mg/kg) in forced swim and tail suspension
tests without any persistent antidepressant effect (Popik
et al., 2008), many preclinical studies have recently
focused on understanding the molecular mechanisms
underlying the rapid-onset prolonged antidepressant
effects. These studies show that plasticity-related pathways, especially the BDNF signaling pathway, are
influenced by ketamine treatment (Duman and Voleti,
2012; Kavalali and Monteggia, 2012; Reus et al., 2014;
Yang et al., 2014; Zhou et al., 2014). These effects are
dependent on the mammalian target of rapamycin
(mTOR) signaling pathway (Li et al., 2010a), because
they can be blocked by rapamycin. This effect could be
mimicked by GluN2B subunit-containing NMDAR
antagonist Ro 25-6981 [(aR,bS)-a-(4-hydroxyphenyl)b-methyl-4-(phenylmethyl)-1-piperidinepropanol
maleate], which induced antidepressant-like behavioral effects. mTOR is a serine-threonine protein kinase,
the subtypes of which, mTORC1 and mTORC2, form
active protein complexes with Raptor or Rictor, respectively. mTORC1 via p70S6K promotes cell growth,
mRNA biogenesis, and the translation of ribosomal
proteins. mTORC2 via Rictor activates and phosphorylates Akt to enhance cell survival, relying upon PKCa
for cytoskeleton remodeling, and controlling cell migration through the Rac guanine nucleotide exchange factors
and through Rho signaling (Laplante and Sabatini, 2009;
Buffington et al., 2014; Maiese, 2014). A single dose of
ketamine was reported to upregulate BDNF via activation (phosphorylation) of 59 adenosine monophosphateactivated protein kinase in the rat HC (Xu et al., 2013).
Rats receiving ketamine (75 mg/kg) on postnatal day
7 (P7) developed cognitive impairments in adulthood
(Huang et al., 2012). These effects were associated with
suppressed expression of pPKC, pERK1/2, and Bcl-2 with

unchanged tPKC or tERK levels during postnatal phase.

Long-term ketamine treatment in adult mice may cause
delayed and persistent upregulation of subcortical
DAergic system via a mechanism involving the BDNF
pathway (Tan et al., 2012b). Whereas acute and chronic
treatment of ketamine caused an antidepressant-like
effect in the forced swim test, only chronic treatment
(0.5 mg/kg/day for 10 days) increased AMPAR/NMDAR
density ratio in the HC of the depressed female
Wistar-Kyoto rats (but not in control Wistar rats) at 20
hours after the treatment (Tizabi et al., 2012). Synaptic
potentiation appears to underlie the ketamine efficacy
also in depressive patients, as suggested by increased
cortical excitability measured by means of magnetoencephalography (Cornwell et al., 2012). Importantly,
AMPAR antagonists have been shown to prevent the
antidepressant effects of ketamine in rodents, suggesting
that AMPAR activation is required for more persistent
antidepressant effects that are at least partly mediated
by upregulation of mTOR and BDNF pathways (Koike
et al., 2011; Koike and Chaki, 2014; Zhou et al., 2014).
Stereomers (R,S) of ketamine and its metabolites
norketamine and (2S,6S)-hydroxynorketamine increase
phosphorylation of mTOR and its downstream targets
Akt, ERK1/2, 70S6K, and 4E-BP1 in a cell culture model
(Paul et al., 2014b). As mentioned earlier, the activation
of mTOR pathways is crucial for synaptic plasticity.
Pharmacokinetic studies in treatment-resistant bipolar
patients show that norketamine is the initial but not
the main metabolite and that other metabolites, namely
dehydronorketamine, (2S,6S;2R,6R)-hydroxynorketamine,
and hydroxyketamine are detected during the first
48 hours (Zhao et al., 2012). These metabolites may
play a role in the antidepressant effects. Intriguingly,
higher plasma levels of (2S,5S;2R,5R)-hydroxynorketamine
were related to nonresponse to ketamine in bipolar
disorder patients (Zarate et al., 2012a), some metabolites being perhaps responsible for psychotomimetic
effects of ketamine.
Ketamine and some metabolites have affinity to a7nAChRs at relevant concentrations and behave as negative allosteric modulators (Moaddel et al., 2013).
Furthermore, several neuropharmacological studies have
shown direct and indirect effects of ketamine on other
neurotransmitters. A very recent study showed that
ketamine treatment-associated restoration of plasticity
in the ventral subiculum-NAc shell is caused by activation of D1 receptors (Belujon and Grace, 2014). In vitro
receptor binding studies show that ketamine has very
similar affinity to NMDARs and the high-affinity state
of the D2 receptors (where it works as an antagonist)
and a slightly lower affinity to 5-HT2 receptors (Kapur
and Seeman, 2001, 2002; Seeman and Kapur, 2003;
Seeman et al., 2005). Ketamine (40 mg/kg) pretreatment
prevented bicuculline-induced seizures and reversed
changes in [3H]QNB binding to muscarinic receptors
induced by bicuculline, showing the roles of muscarinic

Drug-Induced Neuroplasticity

and GABAA receptors (Schneider and Rodriguez de

Lores Arnaiz, 2013). Indeed, ketamine, but not PCP or
MK-801, acts as a positive modulator at specific cerebellar extrasynaptic GABAA receptor populations (Hevers
et al., 2008). An earlier study showed that ketamine
inhibits muscarinic signaling in CHO cells as observed
from intracellular Ca2+ release in response to the agonist
acetyl-b-methylcholine (Durieux, 1995). Finally, ketamine has been shown to inhibit the inward pacemaker
current Ih, which is mediated by ketamine binding to
hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (HCN1) subunits in forebrain neurons
(Chen et al., 2009; Zhou et al., 2013). HCN1-KO mice are
less sensitive to ketamine-induced hypnosis (Chen et al.,
2009), indicating that this mechanism may explain the
high-dose anesthetic effects, but no data are available on
whether this mechanism is involved in other behavioral
or neuroplasticity-inducing effects of ketamine. It is
noteworthy that all these studies draw parallels to the
anesthetic dose levels and not the subanesthetic antidepressant dose levels.
Ketamine has strong and prolonged effects on neuronal synaptic physiology. In conscious rats, ketamine
induces synaptic depression in the Schaffer collateralCA1 pathway sustaining beyond 4 hours but normalizing by 24 hours (Duan et al., 2013). Ketamine effects on
memory impairment were anyway predicted to last for
days or even weeks, because the long-lasting synaptic
change is expected to influence protein synthesis and
gene expression. Ketamine and PCP prevent the LTP in
the CA1 region in response to cornu ammonis stimulation in the HC of anesthetized rats (Stringer and
Guyenet, 1983), and, in agreement, a recent in vitro
study showed that ketamine, at its antidepressant
concentration level, negatively modulated both LTP
and LTD in CA1 of juvenile rats (Izumi and Zorumski,
2014). LTD inhibition and enhancement of somatic
EPSPs occurred shortly after ketamine administration,
whereas modulation of LTP occurred after 2 hours or
later. Clinically relevant micromolar concentrations of
ketamine dose dependently decreased LTP without
affecting paired-pulsed facilitation in Schaffer collateralCA1 pyramidal neuron synapses in a mouse HC slice
preparation, but higher concentrations affected basal
excitatory synaptic transmission and presynaptic
volley amplitude (Ribeiro et al., 2014). In a model for
psychosis, administrations of ketamine (20 mg/kg s.c.
given six times, once every 2 hours.) on P4-7 impaired
LTP at 34 weeks of age when recorded in slices from
the anterior cingulate cortex, which was accompanied
by increased AMPAR-mediated excitatory transmission
and decreased GABAergic inhibitory transmission
(Wang et al., 2014).
Ketamine in high anesthetic doses is thought to be
neurotoxic in developing brain of rodents and nonhuman
primates and in selected regions of the mature nervous
system (Olney et al., 1989; Slikker et al., 2007; Wang

945

et al., 2013a), and chronic ketamine treatment in mice

(6 months of daily 30 mg/kg i.p.) caused persistent
damage in brain function as observed from deterioration
in neuromuscular strength and nociception (Sun et al.,
2011). A case report suggested that chronic ketamine use
could impair memory and synaptic plasticity (Jansen,
1990). Furthermore, one MRI study provided anecdotal
evidence of brain atrophy (affecting both gray and white
matter) in the prefrontal, parietal, occipital, limbic
cortical regions, brain stem, and striatum after 24 years
of use in some ketamine-dependent subjects, although no
clear conclusions can be drawn from this study because of
the lack of statistics and a control group (Wang et al.,
2013b).
The psychedelic effects of ketamine may cause psychologic dependence that is cyclical in nature like cocaine and
amphetamine but has been described to be devoid of any
clear withdrawal syndrome (Jansen and DarracotCankovic, 2001). However, recent studies have shown
withdrawal effects from ketamine use. Female ketamine
users may show more severe withdrawal-associated
cognitive impairment than male users (Fattore et al.,
2009; Chen et al., 2014). Furthermore, in humans the
abuse potential of oral ketamine (65 and 100 mg) is robust
enough to have it being suggested as a positive control for
evaluating abuse potential of other psychedelic compounds (Shram et al., 2011). Ketamine intake is higher
in rats that were transferred to SA chambers during the
test sessions than in rats that also were housed in those
chambers, indicating the significant influence of the
setting on ketamine taking (De Luca and Badiani,
2011). Withdrawal of ketamine after 5 days of high dosing
(twice daily 150 mg/kg oral doses) in male cynomolgus
macaques increased activity and stereotypic behaviors,
including head bobbing, repetitive grooming, repetitive
body/limb or hand movements, and repetitive nail biting
during the withdrawal period (Walgren et al., 2014).
Withdrawal syndrome has also been frequently reported
in rodents. Subchronic ketamine (10 mg/kg twice daily for
10 days) in rats causes persistent working memory
impairment in the delayed spatial win-shift task after
a withdrawal for 10 days (Enomoto and Floresco, 2009).
Chronic administration (100 mg/kg/day i.p. for 10 days) of
ketamine in mice produces hyperactivity, enhanced
immobility period in forced swim test, and reduced
latency period in passive avoidance test that persisted
at least for 10 days after the withdrawal (Chatterjee et al.,
2011). Notably, all these studies used high ketamine
doses and/or models of prolonged abuse, indicating
stronger neuroadaptation in that situation than in lowdose antidepressant treatment studies. In contrast, in
clinical settings ketamine has been shown to reduce
cravings in heroin addicted patients when dispensed in
combination with psychotherapy sessions (Krupitsky
et al., 2002).
In summary, ketamine produces strong dose-dependent
behavioral and neurochemical effects. At low doses, it

946

Korpi et al.

produces significant changes in gene expression, resulting in enhanced synaptic plasticity that is likely to be
related to its rapid-onset antidepressive action in both
animal models and humans. On the other hand, high
doses of ketamine impair neuroplasticity and may cause
neurotoxic effects. Finally, in terms of behavior, both
addictive and antiaddictive properties of ketamine have
been described. It is therefore of interest to compare and
contrast the effects of ketamine with that of the second
commonly used NMDAR antagonist, PCP.
2. Phencyclidine. PCP, an NMDAR antagonist and
dissociative anesthetic, long known for its delirium- and
thought disorder-inducing (cognitive deficits) properties (Javitt and Zukin, 1991; Domino and Luby, 2012)
can acutely dissociate the CNS from peripheral sensory
input and induce metabolic hypofunction in several
brain regions, including the FC, HC, and thalamus.
PCP acts on many mechanisms that have been reported
to underlie its neuropharmacological and neurotoxicological effects. At the receptor level, it has a high affinity
to NMDA, 5-HT2A, and D2 receptors (Yamada et al.,
1999; Kapur and Seeman, 2002; Seeman et al., 2005,
2009). Sigma-1 receptors are involved in cognitive
deficits associated with PCP treatment in rodents
(Hashimoto et al., 2007; Kunitachi et al., 2009). At the
functional level, PCP impairs LTP in both in vivo and in
vitro systems (Stringer et al., 1983), e.g., PCP (and
ketamine) prevents both LTP and LTD in rat perforant
path-dentate gyrus synapses (Tizabi et al., 2012).
NMDAR antagonists, such as 2-amino-5-phosphovaleric
acid, N-acetyl-aspartyl-glutamate, and PCP, prevent
both LTP and primed burst potentiation, produced by
variants of electrical stimulation modeling plasticity, in
the CA1 area of rat HC slices (Wiescholleck and
Manahan-Vaughan, 2013; Xu et al., 2013). Subchronic
PCP treatment to rats caused impaired LTP in the lateral
amygdala and Schaffer collateral to HC-CA1 pathway
and marked increases in the NMDAR and AMPARmediated currents in the lateral amygdala (Pollard
et al., 2012).
Effects of PCP in rodents are especially strong and
persistent when given during brain development. Administration of PCP to pregnant rats during gestational
days 1220 days caused a decrease in PCP binding sites
in the fetal brains (Ali et al., 1988, 1989). The prenatal
administration (embryonic days 1218) of PCP (5
20 mg/kg) caused an increased response to PCP-induced
ataxia and an increased number of [3H]PCP binding
sites in the striatum and cortex of the offspring (Fico
and Vanderwende, 1989). Early oligodendrocyte progenitor cell markers were decreased in rat brains prenatally exposed to PCP (10 mg/kg), suggesting that
surviving cells are arrested at an immature stage,
which might have implications for the role of glutamate
and glutamate receptors in white matter abnormalities
in neurodevelopmental disorders (Lindahl et al., 2008).
These findings were strengthened by another recent

report on prenatally PCP-treated mice, demonstrating

aberrant gene expression (Notch2 and Ntn1) and
consequential decrease in the density of glutamatergic
neurons in the PFC, deficits in cognitive memory, and
sensorimotor gating at adulthood (Toriumi et al., 2012).
Prenatal PCP treatment (20 mg/kg) in mice induced
hypersensitivity to a low dose of PCP (3 mg/kg) in
locomotor activity and impairment of recognition memory in the novel object recognition test at the age of
7 weeks and reduced the phosphorylation of GluN1
subunit, although it increased the expression of this
subunit (Lu et al., 2010b). Prenatal PCP (5 mg/kg)
treatment caused impairment in recognition memory in
a novel object recognition test, enhanced locomotion in
a forced swim test, reduced the extracellular glutamate
level, and increased the expression of a glial glutamate
transporter in the PFC at 8 weeks of age (Lu et al., 2011).
Likewise, prenatal administration of PCP (10 mg/kg)
showed disruption of acquisition of passive avoidance
response and pole-climbing avoidance response
(Nabeshima et al., 1988). 5-Bromo-2-deoxyuridinelabeled newborn cells in the dentate gyrus granule cell
layer were significantly increased in rat offspring that
were subjected to prenatal exposure of PCP (Tanimura
et al., 2009). Prenatal and neonatal exposure of PCP
caused increased Bmax for muscarinic cholinergic receptors in the HC and reduced performance in HC-related
radial arm and water maze tasks (Yanai et al., 1992).
A single administration of PCP caused an increase in
cataleptic freezing and sporadic recurrences of backing
up and weaving behavior for up to 21 days in adult rats
(Haggerty et al., 1984). In rats, PCP initially also
reduces the brain weight, and, interestingly, withdrawal from PCP causes a transitory rebound associated with increased molecular layer depth and number
of synapses in the occipital cortex, suggesting a transitory burst of synaptogenesis (Brooks et al., 1997). After
a 72-hour withdrawal from PCP, sensitized locomotor
activation, a marked increase in GluN1 subunit mRNA
in several brain regions, including the FC and anterior
striatum, were detected (Wang et al., 1999). Furthermore, NMDAR-stimulated DA release was not affected
by PCP treatment, but the inhibition of this release by
NMDAR blockers (PCP, 7-chlorokynurenic acid, and
DL-2-amino-5-phosphovaleric acid) was blunted by
chronic PCP, indicative of tolerance. Most likely, PCP
treatment alters the subunit stoichiometry of NMDARs
that may contribute to behavioral plasticity (Wang
et al., 1999). Although there seems to be a discrepancy
between the persistent behavioral deficits (rotarod and
open field tests) and the amount of cell loss in relation to
the time of maximal prenatal PCP effect, exposure to
PCP increases agoraphilic cells in the entorhinal cortex
and subiculum, but reduces them in the ventromedial
hypothalamus, indicating that neurodegenerative and
antiapoptotic effects are dependent on the brain region
(Jebelli et al., 2002). Postnatal (P515) phencyclidine

Drug-Induced Neuroplasticity

disrupts water maze performance in adult rats, which

was associated with maximal [3H]MK-801 binding
(Bmax) in the HC and FC (Sircar, 2003), although similar
treatment reduced NMDA receptor expression in juvenile rats. Male rats treated with PCP (8.7 mg/kg s.c.) on
P7, 9, and 11 showed slight impairment in performing
a spatial reference memory task and strong impairment
in reversal and spatial working memory tasks (Andersen
and Pouzet, 2004). A similar perinatal treatment
schedule with 10 mg/kg of PCP induced disruption of
cognition as tested in progressive ratio operant schedule
task beyond postnatal 120 days (Wiley and Compton,
2004). PCP administration (10 mg/kg) on P2, 6, 9, and 12
caused a constellation of anatomic changes in rats at
early adulthood (P70), because it reduces densities of
principal neurons in the CA3 and DG of the HC, those
of interneurons in all cortical and HC regions, density
of reelin- and somatostatin-positive cells, and increases
the number of perisomatic inhibitory terminals around
the principal cells in the motor cortex and HC dentate
gyrus (Radonjic et al., 2013). These changes were
correlated with increased expression of neuregulin-1,
a protein involved in synaptic development and schizophrenia (Mei and Xiong, 2008; Shamir et al., 2012), in
the cortex and HC.
Subchronic PCP treatment (twice a day for 7 days)
followed by 7 days of abstinence causes significant
impairment in the reversal phase of a operant reversal
learning paradigm, demonstrating a persistent cognitive deficit (Abdul-Monim et al., 2006). The deficit was
reversed by acute treatments with atypical antipsychotic compounds ziprasidone, olanzapine, and clozapine.
PCP withdrawal impaired performance in object-placecontext task in rats, which was reversed by donepezil
but not by clozapine (Le Cozannet et al., 2010). Subchronic PCP treatment induced a persistent deficit in
novel object recognition that was attenuated by lurasidone (a potent 5-HT1A partial agonist, 5-HT2A antagonist), tandospirone (weak D2 antagonist), and F15599
(selective postsynaptic 5-HT1A agonist), and interaction
studies with these various ligands showed that 5-HT1A
agonism was adequate to attenuate the PCP-induced
effects (Horiguchi and Meltzer, 2012). These deficits
were also reversed by D1R agonism, the effect of which
was facilitated by 5-HT1A and mGlu2/3 receptor signaling (Horiguchi et al., 2013). Recently, Lu AE58054 (2-(6fluoro-1H-indol-3-yl)-N-[[3-(2,2,3,3-tetrafluoropropoxy)
phenyl]methyl]ethanamine), a 5-HT6 receptor antagonist, was found to reverse subchronic PCP-induced
deficits in novel object recognition test (Arnt et al.,
2010). It is not known whether any of the drug treatments can produce persistent reversal of subchronic
PCP effects, but, interestingly, clozapine and haloperidol prevented the metabolic hypofunction and the
reduced Pv expression in several brain regions in rats
treated intermittently with PCP (Cochran et al.,
2003).

947

In the PFC of rats, acute PCP treatment caused

significant changes in about 500 genes, including many
that are associated with neural plasticity (Kaiser et al.,
2004). Single and repeated administrations in adult
rats causes transient BDNF upregulation in the corticolimbic system, and subchronic postnatal administration
of PCP increased BDNF (protein and mRNA) in the HC
and entorhinal cortex that sustained till 8 weeks of age,
being responsible for the persistent decrease in the
prepulse inhibition in adults (Takahashi et al., 2006).
PCP treatment (20 mg/kg/day) for 14 days caused
reduction in the levels of pERK1/2, pCaMKIIa, and
pCREB in the PFC (Molteni et al., 2008). Two injections
of PCP reduced Pv and GAD67 levels in the PFC, and
this effect persisted after 10 days (Amitai et al., 2012). A
single injection of PCP (10 mg/kg) to rats on P7 caused
selective reduction in Pv-containing, not calretinin- or
calbindin-containing, interneurons in cortical areas in
early adulthood (P56) (Wang et al., 2008a). A persistent
decrease in the number of PFC spine synapses, in
parallel to the cognitive deficits, was evident with twice
daily injection of 5 mg/kg of PCP for 7 days (Elsworth
et al., 2011b). These PCP effects on gene regulation are
important examples of the widespread actions of PCP
on neural tissue, which appear to produce long-term
changes in the nervous system. An in vitro study
employing cortical neuronal culture showed that PCP
causes a transient increase within 3 hours followed by
a decrease in the intracellular BDNF, whereas activation of TrkB receptors and downstream cascades
(MAPK/ERK1/2 and PI3K/Akt) were decreased. The
number of synaptic sites and expression of synaptic
proteins were reduced 48 hours after treatment, without affecting the cell viability (Adachi et al., 2013).
Interestingly, exogenous BDNF completely reversed
the downregulating effect of PCP on the TrkB signaling
and synaptic protein expression (Adachi et al., 2013).
Postnatal treatment (P7, 9, and 11) with PCP (10 mg/kg)
reduced Nrg1 and erbB4 expression and phosphorylated Akt during development in the cerebral cortex (du
Bois et al., 2012) and displayed hyperactivity in holeboard and forced swim tests in adulthood (du Bois et al.,
2008).
Cognitive impairment and anatomic and neurochemical effects after PCP administrations have also been
reported in mice. Repeated administration of low doses
(0.52.0 mg/kg) of PCP causes cognitive impairment
associated with alterations in Arc and spinophilin
mRNA expression in the HC, striatum, and retrosplenial cortex (Beraki et al., 2009). Repeated PCP treatment (10 mg/kg for 10 days) decreased the expression of
Pv and synaptophysin mRNA in the mouse PFC and
increased basal Arc mRNA expression (Thomsen et al.,
2009). Lastly, in primates, chronic PCP (0.3 mg/kg twice
a day for 14 days) caused a 40% reduction in Pvcontaining axo-axonic structures in the PFC (Morrow
et al., 2007). PCP treatment in primates also leads to

948

Korpi et al.

persistent deficits of cortical DA (for 9 days) (Jentsch

et al., 1999). Subchronic PCP treatment (0.3 mg/kg
twice a day for 14 days) caused a reduction in the
number of asymmetric spine synapses in layer II/III of
the dorsolateral PFC that may perhaps account for
the cognitive dysfunction (Elsworth et al., 2011a).
Thus, persistent effects of PCP appear to rely at least
in part on its cortical neurotoxicity and neuregulin
downregulation.
In terms of addiction potential, PCP is also abused by
humans (Crider, 1986). Rats self-administer PCP as well
as MK-801 and the competitive NMDAR antagonist
3-((+/2)2-carboxypiperazin-4yl)propyl-1-phosphate into
the NAc and PFC in a DA-independent manner, unaffected by D2 receptor blockade by sulpiride (Carlezon
and Wise, 1996). Many NMDAR antagonists have often,
but not in all studies, dose dependently induced CPP in
rodents (Tzschentke, 2007) and PCP, at least somewhat,
lowered the threshold for lateral hypothalamic selfstimulation (Kornetsky and Esposito, 1979).
PCP, like ketamine, has strong effects on synaptic
plasticity and is capable of altering LTD and LTP as
well as the expression of genes known to be involved in
neuronal plasticity, effects that are often associated
with behavioral abnormalities and changes in cognition
and prepulse inhibition as well as the development of
SA of the drug. This leads to the question of how PCP
and ketamine compare with the prototypical and highly
selective NMDA antagonist MK-801.
3. Dizocilpine, a Prototypic Noncompetitive N-methylD-aspartate Receptor Antagonist. Unlike ketamine
and PCP, the recreational use of dizocilpine (MK-801)
has been very limited, although it has been reported to
have clear psychoactive effects comparable with other
NMDAR antagonists, suggesting that MK-801 has
somehow remained undesirable or unobtainable for
prospective users (Morris and Wallach, 2014). However,
it is the most selective of the noncompetitive inhibitors
of NMDARs and is known to cause behavioral sensitization (Vanderschuren et al., 1998).
The long-lasting and persistent effects of MK-801 on
synaptic plasticity and memory in rodents have been
recently reviewed (Wiescholleck and ManahanVaughan, 2013). Administration of MK-801 to rats causes
facilitation of LTP at the HC CA1-subiculum synapses 24
hour after treatment, suggesting metaplasticity (Buck
et al., 2006). However, a 4-week treatment reversed the
magnitude of LTP to control level. Intrathalamic administration of MK-801 changes local field potentials and
paired-pulse facilitation in rats, indicative of changes in
short-term plasticity (Kiss et al., 2011). After application
of MK-801, homosynaptic LTP of the direct cortical input
to CA1 was abolished for at least 1 week, with partial
recovery after 4 weeks (Whrl et al., 2007). MK-801
treatment causes long-lasting potentiation in HC-mPFC
pathway and impairments in mPFC-dependent cognitive
flexibility and HC-mPFC-dependent working memory in

rats, which were reversed by mGlu2/3 receptor agonist

LY379268
[(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]
hexane-4,6-dicarboxylic acid] (Blot et al., 2013). Thus, it
is important to take into consideration the strong effects
of MK-801 treatments themselves on neuroplasticity and
metaplasticity, when one wants to assess the roles of the
NMDARs in plasticity processes by using this antagonist.
Furthermore, in rodents, high neurodegenerative doses
of MK-801 induce prolonged hypothermia, which can
acutely affect cognitive behavior but may not as such have
lasting impairing effects on cognition (Zajaczkowski et al.,
2000).
A small study showed that primates with the history
of PCP use, but not those with a history of cocaine use,
self-administered MK-801 (Beardsley et al., 1990;
Steinpreis et al., 1995). MK-801 also reversed the
withdrawal effects of PCP (Carroll et al., 1994). In
rodents, MK-801 elicits CPP by itself (Layer et al.,
1993). Importantly, it inhibits CPP induced by METH
(Kim and Jang, 1997) and morphine (Tzschentke and
Schmidt, 1995; Kim et al., 1996) and blocks the
persistent neuroplasticity in VTA DA neurons and the
blunting of d-AMPH sensitization after a single dose of
BZs (Heikkinen et al., 2009; Panhelainen et al., 2011).
Interestingly, combination treatment of the rewarding
doses of NMDA and MK-801 did not result in CPP
(Panos et al., 1999). MK-801 significantly reduces fixed
ratio maintained operant responding for cocaine (Pierce
et al., 1997), but it can reinstate extinguished cocaineseeking behavior (De Vries et al., 1998) and disrupt the
reconsolidation of a cocaine-associated memory for CPP
(Brown et al., 2008).
MK-801 produces variable effects on DA release,
because systemic injection of MK-801 significantly suppressed striatal DA release in conscious rats, which was
not related to its behavioral effects (Kashihara et al.,
1990). Infusion of MK-801 into the NAc prevented
intrapallidal morphine-induced NAc DA release
(Anagnostakis et al., 1998). Its systemic administration,
however, increased DA release in the NAc, which could
be prevented by prazosin, an a1 adrenoceptor antagonist (Mathe et al., 1996). Systemic administration or
infusion into the PFC, ventral pallidum, NAc, or
striatum increased local DA release (Wedzony et al.,
1993; Hondo et al., 1994; Kiss et al., 1994; Kashiwa
et al., 1995; Schmidt and Fadayel, 1996; Yan et al.,
1997; Mathe et al., 1999; Kretschmer, 2000). In rodent
striatal slices, MK-801 attenuated ischemia-, hypoxia-,
hypoglycemia-, and L-glutamate-induced DA release
(Milusheva, 1992; Kim et al., 1995; Antonelli et al.,
1997), suggesting neuroprotective effects. MK-801induced behavioral sensitization was associated with
changes in the kinetics of DA release characterized by
a delayed (after 2 hour) release in the PFC (Cui et al.,
2014). But MK-801 failed to alter the striatal DA release
caused by METH (Baldwin et al., 1993), and a few other
reports showed that MK-801 had a weak or no effect on

Drug-Induced Neuroplasticity

pallidal, accumbal, or prefrontal cortical DA release

(Wedzony et al., 1993; Saulskaya and Marsden, 1995;
Wheeler et al., 1995; Druhan et al., 1996; Takahashi
et al., 1996; Anagnostakis et al., 1998; Callado et al.,
2000). MK-801 treatment reversed the decrease in
striatal DA, DOPAC (3,4-dihydroxyphenylacetic acid),
and HVA (homovanillic acid) caused by METH (Boireau
et al., 1995), and d-AMPH pretreatment prevented MK801-induced striatal DA release (Nash and Yamamoto,
1993). In summary, although MK-801 has the potential to
facilitate the release of DA, its effects are complex, most
likely due to different roles of the NMDARs in different
synapses, neuroplasticity, and regulation of neuronal
circuits composed of inhibitory and excitatory neurons
and glial cells, all being responsive to glutamate.
MK-801 has profound effects on gene expression in
the rodent brain. For example, it decreases BDNF
mRNA in the HC and superficial layers of cerebral
cortex and increases BDNF mRNA in the middle layer
(single cells) of cerebral cortex, midline thalamic
nuclei, and retrosplenial and medial entorhinal cortices
(Castren et al., 1993). The treatment increases DNA
binding activity of the activator protein-1 complex,
mRNAs of BDNF (Linden et al., 2000), neuronal Src in
superficial layers of the parietal cortex, tyrosine phosphorylation of GlunN2A subunit (Linden et al., 2001),
c-Fos, DFosB, Fra-2, and JunB expression in the entorhinal cortex (Kontkanen et al., 2000; Vaisanen et al.,
2004), possibly related to psychotic effects. Expression
profiling analysis showed that MK-801 regulates ER
proteins Erp29, a stress-inducible liver protein, and (at
higher doses) RTN1, a reticulon, and ABC transporters
involved in small molecule transport, reflecting possible
toxicity in the cingulate and entorhinal cortices (Toronen
et al., 2002).
The mechanisms involved in MK-801-induced neurotoxicity have been described and include 1) in the adult
brain, occurrence of paradoxical neurodegeneration,
disinhibition of glutamatergic and cholinergic projections of the cerebral cortex due to blockade of NMDARs
on inhibitory neurons in many subcortical regions
(Farber et al., 2002; Li et al., 2002), and 2) in the
developing brain, apoptotic neurodegeneration (Olney
et al., 1989; Dzietko et al., 2004) that is also reported for
ketamine (Zou et al., 2009; Liu et al., 2011) and PCP
(Rahbar et al., 1993; Deutsch et al., 1998). The MK-801induced toxicity in adult rats can be prevented by
injections of scopolamine and NBQX (6-nitro-2,3dioxo-1,4-dihydrobenzo[f]quinoxaline-7-sulfonamide)
(into the cerebral cortex) and clonidine (into basal
forebrain) (Farber et al., 2002) and by systemic scopolamine (Shirakawa et al., 2013), erythropoietin (partial
effect, counteracting the reduction in BDNF and GNDF
expression by NMDAR antagonists)(Dzietko et al.,
2004), and ethanol (Farber et al., 2004), but not by
increased BDNF (Vaisanen et al., 2003). Neurotoxicity
by PCP and ketamine can also be attenuated by

949

diazepam and haloperidol (Nakao et al., 1996; Nakki

et al., 1996). It is noteworthy that ethanol-antagonism
of NMDARs induces more neurotoxicity in developing
than adult rat brain, presumably due to the inhibitory
GABA mimetic effects of ethanol in adult brain (Olney
et al., 2000, 2002). It may also reflect the role of the
NMDARs in neuronal development and excitotoxicity,
both of which can be blocked in cultured neurons by
ethanol (Wegelius and Korpi, 1995).
In summary, MK-801 as a prototypic NMDAR antagonist produces widespread changes in brain gene
expression, which might have prolonged effects on
neuronal function and structure. The high-dose toxicity
of MK-801 and other NMDAR antagonists is associated
with brain region-dependent and time-dependent astrogliosis and microglial activation (Fix et al., 1996; Nakki
et al., 1996). On the other hand, recent work has also
revealed that MK-801 and other NMDAR antagonists
attenuate microglial activation induced by various
drugs and insults (Thomas and Kuhn, 2005; Nair and
Bonneau, 2006), which may at least partly explain the
neuroprotective effects of these drugs. Interestingly,
MK-801 and cocaine have distinct effects on gene
expression, with the interactions between their effects
being complex (Storvik et al., 2006).
4. Conclusions. Potent NMDAR antagonists are
drugs that affect neuroplasticity processes in the brain,
lead to addiction, and suffer from induction of psychotomimetic effects and thought-impairing cognitive deficits
in many subjects, with a high potential to induce
paradoxical neurodegeneration. Ketamine and its analogs are now studied for the rapid, long-lasting antidepressant effect, with early results indicating strong
activation of neuronal plasticity mechanisms. Phencyclidine and dizocilpine are used in preclinical settings to
induce a model of adult psychosis by adolescent exposure or to assess the role of NMDARs in behavior and
physiologic functions, respectively.
G. Opioid-Induced Neural Adaptations
Opioids are widely used as powerful analgesic agents
that are also highly addictive. A sizable proportion of
individuals that either misuse opioids or use them
clinically become addicted. With chronic use, adaptive
neural mechanisms are initiated at various levels of
neural organization, leading to both short-term and
protracted changes in the functioning of opioid-sensitive
neurons and neural networks (Williams et al., 2001;
Christie, 2008; Dacher and Nugent, 2011b; Lutz and
Kieffer, 2013). Some of these adaptations, such as opioid
tolerance, have been intensively investigated. However,
the neural mechanisms underlying protracted features of
withdrawal, such as opioid seeking and relapse contributing to the compulsive features of opioid dependence,
still remain largely unknown. In the following sections,
we will focus on describing the most important findings
related to chronic opioid use, including the mechanisms of

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Korpi et al.

opioid tolerance, the withdrawal syndrome, and opioidinduced synaptic plasticity.

Opioids exert their actions through three major
receptor subtypes, m, d, and k, opioid receptors that
were first identified by pharmacological tools and later
verified by molecular cloning (Goldstein and Naidu,
1989; Evans et al., 1992; Kieffer et al., 1992; Reisine and
Bell, 1993). Further diversification of opioid receptor
functions may be achieved by alternate splicing, posttranslational regulation, or receptor dimerization. All
opioid receptors are GPCRs, coupled with pertussis
toxin-sensitive G proteins Gi/o (Connor and Christie,
1999). The coupling profile to G proteins of all three
opioid receptors is similar, including inhibition of AC,
activation of potassium conductance, inhibition of calcium conductance, and inhibition of transmitter release
(Williams et al., 2001). Opioid receptors and their
mRNAs display distinct anatomic distribution in neuronal systems, as well as paracrine and exocrine tissues
important for opioid drug actions (Mansour et al., 1987,
1995; Zhu et al., 1998).
The primary target of most opioid drugs is the m
receptor, through which the addictive properties of
opioids are also mediated. The levels of neural adaptations to chronic opioids can be conceptualized as 1) loss
of the m receptor coupling to its cellular effectors, 2)
adaptations in the intracellular signaling cascades, 3)
systems feedback adaptations in neuronal and glial
networks, and 4) changes in synaptic plasticity (Christie,
2008).
1. Desensitization and Internalization in Opioid
Tolerance and Dependence. Development of opioid
tolerance is partly dependent on a partial loss of
capacity of the m receptor to signal to its intracellular
effectors (Kieffer and Evans, 2002; Christie, 2008;
Allouche et al., 2014). This "receptor tolerance" can be
achieved by different mechanisms, primarily by decreased cell surface expression of m receptors and/or
attenuation of coupling efficacy of the surface receptors.
Because chronic morphine administration generally
produces little changes in either m receptor mRNA or
protein expression (Patel et al., 2002), most research
has focused on the reduced coupling of m receptor to its
effectors. However, considering the limited reduction in
potency of opioid agonists in functioning neurons after
prolonged morphine exposure (Williams et al., 2001), it
does not seem likely that behavioral opioid tolerance
can fully be ascribed to decreased receptor coupling.
Tolerance at systems levels also involves interaction of
mechanisms of tolerance at molecular, cellular, and
neural network levels. The magnitude of m receptor
uncoupling from G protein activation has been found to
differ in different neuron types, where m receptors are
coupled with diverse signaling systems (Sim-Selley
et al., 2000).
For receptor uncoupling, the mechanism of opioid
receptor desensitization and internalization are

assumed to resemble the model established for the

b2-adrenergic receptor. In this model, agonist activation
induces m receptor phosphorylation by G proteincoupled receptor kinase 2, which increases the affinity
of the receptor to arrestin 3 (Arr3). The binding of Arr3
uncouples the receptor from G protein signaling (desensitization) and initiates the receptor sequestration
and internalization by an Arr3- and dynamindependent mechanism (Gainetdinov et al., 2004). The
importance of this sequence of events was tested using
Arr3-KO mice (Bohn et al., 2000). In these mice, chronic
morphine treatment did not induce desensitization of
the m receptor and failed to produce either acute or
chronic antinociceptive tolerance. However, these mice
still became physically dependent on morphine and
exhibited upregulation of AC activity that has been
used as a cellular marker of opioid dependence (see
below), suggesting that antinociceptive tolerance and
physical dependence could have different underlying
mechanisms. Although homologous desensitization
thus seems to have a role in morphine tolerance at the
receptor level, the importance of internalization is far
from clear. Compared with other efficacious m receptor
agonists, such as [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin
(DAMGO), methadone, or sufentanyl, morphine has a low
efficacy for producing receptor internalization (Whistler
et al., 1999; Borgland et al., 2003), consistent with its
profile as a partial agonist. Therefore, the effects of
chronic morphine on desensitization are probably more
important than internalization for the functional uncoupling of the receptor.
2. Cellular Signaling in Opioid Tolerance and
Dependence. Behavioral tolerance can also result from
mechanisms subsequent to receptor activation that
adapt to restore function in the presence of drug.
Continued presence of an inhibitory agonist leads to
homeostatic compensation of the downstream signaling
systems. Subsequent removal of the agonist can then
lead to a rebound activation of the signaling systems
and cause neural excitation. This overshoot may underlie the initial phases of withdrawal, but could also
lead to more persistent effects of signaling systems that
are reflected in synaptic events or structural changes.
Particularly interesting for opioid-induced alterations
are the signaling systems directly downstream from m
receptor activation, such as the AC-cAMP-PKA cascade
and the MAPK cascades (Christie, 2008). Most likely,
however, the mechanisms underlying chronic opioid
effects are not limited to signaling systems directly
downstream of receptor activation, but could reflect
general homeostatic compensations in response to
enhanced neural inhibition by opioid agonists.
The AC-cAMP-PKA cascade is a well-studied example of the tolerance resulting from compensation. Acute
opioids inhibit AC, but depressed concentrations of
cAMP return to normal during chronic opioid exposure
as the AC activity is upregulated. Upon removal of the

Drug-Induced Neuroplasticity

agonist, this compensatory increase persists and has

therefore been regarded as a cellular marker of withdrawal (Sharma et al., 1975; Williams et al., 2001). This
general picture is complicated by the existence of
several isoforms of AC that could be regulated by
distinct mechanisms (Watts and Neve, 2005). Three of
these isoforms, ACI, ACII, and ACV, are neuronal and
they are highly localized to synapses (Mons and Cooper,
1995). In cell lines and expression systems, ACI and
ACV isoforms were supersensitized by chronic opioid
treatment, but at neuronal tissue levels, the magnitude
of upregulation is rather small, which could be due to
the heterogeneity of cell types, presence of many opioid
receptor subtypes, and AC isoforms (Williams et al.,
2001). However, there is abundant evidence that the
opioid-induced upregulation of the AC-cAMP-PKA cascade in specific synapses in different brain areas could
contribute to neural and behavioral adaptations associated with morphine withdrawal.
Adaptations of the NEergic LC have been implicated
in opioid withdrawal behavior. Acute opioids decrease
LC neuronal activity and inhibit the cAMP signaling
pathway (Duman et al., 1988). Chronic opioids produce
tolerance, demonstrated by upregulation of cAMPdependent PKA during chronic morphine treatment
(Ivanov and Aston-Jones, 2001), suggesting that this
signaling pathway is involved in the withdrawalinduced hyperactivity of LC neurons. The LC hyperactivity may influence the activity of several other brain
areas through widespread efferent projections. The
phosphorylation state of CREB exerts transcriptional
control over a large number of neurotransmitter receptors and signaling molecules. In the LC, overexpression
of the constitutively active CREB mutant aggravated
morphine withdrawal symptoms, whereas the dominantnegative CREB mutant suppressed them (Han et al.,
2006). CREB overexpression did not affect neuronal
firing at baseline, but it enhanced the effects of the AC
activator forskolin, suggesting sensitization of the
cAMP pathway. Therefore, morphine-induced increase
in CREB activity could contribute to adaptations underlying morphine dependence and withdrawal. Similar to the LC, physiologic and biochemical studies have
indicated a role for the periaqueductal gray area (PAG)
in the expression of several withdrawal signs. Because
the inhibition of GABAergic transmission by opioids
causes disinhibition of PAG projection neurons, leading
to activation of the descending pathways, adaptations
in the PAG could be associated with the somatic and
aversive withdrawal symptoms (Bandler and Shipley,
1994). In line with this idea, opioid withdrawal increased inhibitory transmission mediated by GABAA
receptors, which was blocked by PKA inhibitors and
occluded by cAMP analogs (Ingram et al., 1998). It
therefore seems that in the PAG, opioid dependence
reflects m receptor coupling to presynaptic inhibition
in GABAergic nerve terminals via AC- and PKA-dependent

951

processes, with the withdrawal being associated with the

abrupt increase in GABA release.
Opioid-induced adaptations in the nuclei of the
mesolimbic DA pathway, such as the VTA and NAc
that lead to alterations in the DAergic tone, could
potentially modulate the motivational aspects of opioid
withdrawal. In the VTA of morphine-treated guinea
pigs, both inhibitory postsynaptic currents and the
potency of forskolin and the cAMP-dependent protein
kinase to increase these currents were augmented
(Bonci and Williams, 1997), suggesting upregulation
of the cAMP-dependent cascade. Similarly, in the NAc
during withdrawal from chronic morphine, forskolin
activation increased inhibitory transmission, suggesting that opioid dependence induced an opioid-sensitive
cAMP-dependent mechanism that regulates transmitter release and could contribute to opioid withdrawal
(Chieng and Williams, 1998).
3. Novel Mechanisms in Between-systems Adaptations.
Because chronic opioid administration produces alterations in the excitability in opioid-sensitive neurons,
these changes can indirectly induce adaptations in
other neurons and synapses in the circuitry. For
example, this is illustrated by opioid-induced adaptations in the VTA DA neurons that are not primary
targets of opioids. It has also been postulated that
specific systems that functionally oppose the m opioid
receptor signaling could modulate opioid tolerance and
dependence. One of these systems is the cholecystokinin
(CCK) system that has been studied especially in
relation to analgesic effects of m-opioid receptor stimulation (reviewed in Wiesenfeld-Hallin et al., 1999). For
example, CCK peptides, G protein-coupled CCK1, and
CCK2 receptors show complex expression patterns
and interact with a number of neurotransmitter/
modulator mechanisms to both oppose and reinforce
opioid-induced analgesia and anxiolysis within the
PAG (Mitchell et al., 2011). CCK is also strongly
expressed in the VTA (Ballaz et al., 2013) and can
influence drug-induced reward processes. Indeed,
CCK infusion into the NAc attenuated intracranial
electrical self-stimulation in the VTA (Vaccarino and
Koob, 1984). Systemic CCK2, but not CCK1, receptor
antagonism attenuated expression of morphineinduced CPP (Lu et al., 2000; Mitchell et al., 2006)
and naloxone-induced withdrawal symptoms (Lu
et al., 2000). Furthermore, the CCK2 antagonism in
the anterior NAc attenuated morphine-induced CPP,
whereas that in the posterior NAc enhanced the CPP
in a manner dependent on D2 receptors (Mitchell
et al., 2006).
Another important one of these modulating systems
is the dynorphin/k-opioid receptor system that has been
suggested to participate in mediating opposing alterations in behavior and brain neurochemistry that occur
in response to repeated drug use, particularly stimulants and alcohol (Shippenberg et al., 2007). Therefore,

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Korpi et al.

aberrations in this opioid system could also contribute

to the neural dysregulations underlying the development of addiction. In addition, increasing evidence is
accumulating that the opioid receptor-like NOP receptor and its endogenous ligand N/OFQ contribute to
changes in plasticity observed with morphine tolerance
and dependence. In particular, increased antiopioid
activity of the nociceptin system was suggested to
participate in the development of opioid tolerance and
dependence, because either genetic or pharmacological
blockade of NOP signaling prevented them (Ueda et al.,
2000; Chung et al., 2006).
Glial activation is also emerging as a novel modulator
of opioid effects, although glia have mainly been studied
in the context of pain at the spinal level. The glial cells,
particularly astrocytes and microglia in this context,
release several substances that can modulate glianeuron communication and shape neuronal plasticity
(Watkins et al., 2005). Chronic morphine treatment
induces glial activation in many brain areas, including
the spinal cord, cingulate cortex, hippocampus, and
PAG (Song and Zhao, 2001; Hao et al., 2011). Morphine
and other m receptor agonists bind to an accessory
protein of glial toll-like receptor 4 (TLR4), myeloid
differentiation protein 2, and thereby induce TLR4
oligomerization and trigger subsequent glia-mediated
proinflammatory responses. TLR4 activation causes the
release of proinflammatory and neuroexcitatory cytokines, such as tumor necrosis factor-a and interleukin1b (Wang et al., 2012b). Tumor necrosis factor-a has
been shown to modulate neuronal functions in various
ways, including an increase of AMPAR activity, spontaneous and evoked transmitter release, and cell surface expression of AMPARs and NMDARs (reviewed in
Ouyang et al., 2012). Both the opioid-active (2)-naloxone
and (2)-naltrexone and the opioid-inactive isomers
(+)-naloxone and (+)-naltrexone block activation of
TLR4 signaling, providing a means of specifically inhibiting glial activity by the nonopioid isomers (Watkins
et al., 2009). They have been shown to attenuate
morphine analgesic tolerance and withdrawal symptoms
(Hutchinson et al., 2010), as well as opioid addiction-like
behavior, such as morphine-induced CPP, remifentanil
SA (Hutchinson et al., 2012), and abstinence enhancement of cue-induced heroin seeking (Theberge et al.,
2013). However, the potential of (+)-naloxone and
(+)-naltrexone as TLR4 antagonists has been contested
on the basis of in vitro assays (Skolnick et al., 2014).
Further indications of the role of glial cells in morphine
behaviors come from interesting experiments by Schwarz
and coworkers (Schwarz et al., 2011; Schwarz and Bilbo,
2013), who first showed that neonatal handling of rats
(from P2 to P20) strongly decreased the methylation of
the gene encoding the cytokine IL-10 in microgliaenriched brain samples and increased IL-10 expression
in adulthood. This was negatively correlated with
morphine-induced reinstatement of CPP (Schwarz

et al., 2011). On the other hand, subchronic treatment

of rats with morphine in adolescence (P3742), but
not in early adulthood (P5458), strongly facilitated
morphine-induced reinstatement of extinguished CPP
18 days later (Schwarz and Bilbo, 2013). The reinstatement was correlated with increased TLR4 expression in
microglia, suggesting that adolescent morphine exposure produces long-term changes in microglial function
and in sensitivity to drug-induced relapse.
4. Opioid-Induced Changes in Excitatory and Inhibitory Synaptic Plasticity. The compulsiveness of
drug use has been conceptualized to be mediated by
pathologic forms of memory that are based on synaptic
adaptations resembling other forms of activitydependent plasticity, such as LTP and LTD (Kauer
and Malenka, 2007). For example, synaptic plasticity in
the VTA has been suggested to be a common cellular
substrate for abused drugs in the initial phases of drug
addiction. Thus, a single administration of morphine
also induces plasticity in the VTA DA neurons that lasts
long after the administration, as evidenced by increased
ratio of AMPAR/NMDAR currents, which is consistent
with morphine-induced LTP of glutamatergic synapses
onto DA neurons (Saal et al., 2003). In addition, there is
now increasing evidence for GABAergic inhibitory
plasticity after morphine administration. It has long
been known that DA-dependent opiate actions involve
VTA GABA neurons. By inhibiting local GABAergic
interneurons, opiates disinhibit DA neurons (Johnson
and North, 1992), which results in increased DA cell
firing and DA release in the VTA projection areas,
including the NAc.
GABAA receptor-mediated synaptic transmission
onto VTA DA neurons expresses long-term potentiation, known as LTPGABA (Nugent et al., 2007; Niehaus
et al., 2010). This form of LTP has been described as
heterosynaptic, because it requires postsynaptic
NMDAR activation but results from increased GABA
release at neighboring inhibitory nerve terminals.
Activation of NMDARs on postsynaptic DA neurons
produces the retrograde signaling molecule NO, which
in turn activates guanylate cyclase in presynaptic
GABAergic nerve terminals. Increased levels of guanylate cyclase promote potentiation of GABA release,
thereby initiating LTPGABA. Further work showed that
NO-cGMP signaling activates cGMP-dependent kinase
PKG and that NO-cGMP signaling potentiates GABAA
receptor-mediated, but not GABAB receptor-mediated,
synaptic responses (Nugent et al., 2009). Morphine in
vivo blocks LTPGABA by interrupting signaling from NO
to guanylate cyclase and therefore reduces normal
inhibitory control (Nugent et al., 2007).
In addition to LTPGABA, the same GABAergic synapses can also exhibit long-term depression (LTDGABA) in
response to 1-Hz LFS. This form of synaptic downregulation is not dependent on NMDA or CB1 receptors
but on D2-like receptor activation. This D2R activation

Drug-Induced Neuroplasticity

requires a neurochemical signaling via inhibitory

G protein-PKA-inositol phosphate receptor IP3R-Ca2+calcineurin-A-kinase anchoring protein 150 AKAP150
at GABAergic synapses (Dacher et al., 2013). Importantly, LTDGABA is abolished/occluded by a single dose
of morphine 24 hours before the measurements (Dacher
and Nugent, 2011a). Collectively, morphine-induced
changes in LTPGABA and LTDGABA represent forms of
inhibitory plasticity that together with changes in
excitatory synapses provide a mechanism to enhance
mesolimbic DA transmission and thereby increase the
incentive properties of morphine (Dacher and Nugent,
2011b).
More recently, Atwood et al. (2014) found in vitro LTD
of glutamate inputs to the dorsolateral striatum induced by agonists of m, d, and k receptors, with m and d,
but not k, agonists also inducing the LTD in the
dorsomedial striatum. The depression of synaptic responses could be blocked by receptor subtype-specific
antagonists, but once induced and the agonists washed
away, the LTD responses were insensitive to opioid
receptor antagonists. Importantly, a single in vivo dose
of oxycodone occluded the m receptor-LTD and
endocannabinoid-LTD for 2 days. These novel mechanisms may contribute to striatum-dependent behaviors,
such as habit learning.
5. Chronic Opioids and Synaptic Plasticity.
Plasticity associated with chronic opioid exposure could
underlie various aspects of opioid addiction, such as
sensitization, dependence, withdrawal, and opioid seeking. Opioid-induced plasticity in VTA excitatory and
inhibitory synapses could also provide mechanisms for
these chronic opioid effects. Work assessing the alterations in glutamate receptor subunit expression found
that continuously delivered morphine had no influence
on glutamate receptor levels. However, intermittent
morphine administration schedule that has been associated with behavioral sensitization elevated the VTA
GluA1 levels (Fitzgerald et al., 1996). Upregulated
GluA1 subunit levels could contribute to increased
excitability of VTA DA neurons, which was confirmed
by selective viral-mediated increase of GluA1 subunit in
the VTA bringing up a sensitized response to morphine in
locomotion and place preference conditioning (Carlezon
et al., 1997).
Because the pattern of VTA DA neuron firing depends
on excitatory glutamate drive, any adaptive changes in
excitatory synaptic transmission produced by chronic
morphine are reflected in the activity of DA neurons and
could thus also contribute to decrease of mesolimbic
DAergic neuronal activity observed in vivo in morphinewithdrawn rats. Manzoni and Williams (1999) found
that during acute withdrawal from chronic morphine
treatment there was a fundamental change in the
presynaptic regulation of the glutamate release at this
synapse. First, the transduction pathway responsible
for the opioid receptor-mediated inhibition was less

953

sensitive to agents that disrupt the normal inhibition,

including the potassium channels blocker 4-aminopyridine and the lipoxygenase inhibitor baicalein. Second,
they found that in withdrawn animals, the sensitivity of
presynaptic inhibitory control mediated by GABAB and
mGlu2/3 receptors was enhanced. Together, these findings suggested that one of the consequences of withdrawal from chronic morphine could be augmented
presynaptic inhibition of the excitatory inputs to the
VTA DA cells, which would add to the inhibition of these
neurons. Increased GABA release from interneurons
further potentiates the inhibition of VTA DA neurons
during withdrawal (Bonci and Williams, 1997). The
enhanced GABA release appears to be correlated with
physical dependence on morphine, as measured by
somatic withdrawal signs during withdrawal (Madhavan
et al., 2010). As previously discussed, morphine-activated
m receptors do not exhibit substantial endocytosis and
recycling. In a knock-in mouse, in which a genetic change
in the m receptors promotes morphine-induced receptor
desensitization and endocytosis in the VTA GABA interneurons, the increased GABA release onto VTA DA
neurons was abolished during withdrawal. These data
suggest that receptor trafficking is a compensatory cellular mechanism that could modulate synaptic plasticity
produced by chronic opioid administration (Madhavan
et al., 2010).
GABAAergic neurotransmission in the VTA has been
suggested to mediate the switch from the drug-naive to
the dependent and addicted state. A discrete population
of VTA GABAA receptors was shown to undergo a switch
from inhibitory to excitatory in heroin-dependent and
withdrawn rats (Laviolette et al., 2004). The precise
mechanism of this transformation is not known, but it
seems to be mediated by the BDNF, as demonstrated by
promotion of the switch by BDNF injection into the VTA
and attenuation of the aversive motivational states of
heroin withdrawal by local knockdown of the BDNF
receptor TrkB expression (Vargas-Perez et al., 2009,
2014). The cellular phenotypes of the circuit components for this model require still further work in the
VTA and associated areas. More generally, these results
may relate to stress vulnerability and social defeat
stress, which affect drug sensitivities and motivation to
seek reward and drugs (Piazza et al., 1993; Shaham
et al., 1997; Kauer, 2003; Yap et al., 2005; Niehaus et al.,
2010; Ungless et al., 2010; Cabib and Puglisi-Allegra,
2012; McEwen, 2012; Wang et al., 2013c; Walsh et al.,
2014). Recently, BDNF signaling in the NAc has been
shown to be involved in susceptibility to social defeat
stress, actually mediating stress effects, such as social
aversion (Berton et al., 2006). Phasic optogenetic activation of VTA-NAc pathway had no effects on social
interaction and BDNF levels in the NAc in stress-naive
mice, but strongly reduced social interaction and increased BDNF in mice subjected to a subthreshold
social stress (Walsh et al., 2014), confirming that

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stressful events induce prolonged changes in the mesolimbic DA pathway.

In addition to augmentation of VTA presynaptic
mGlu2/3 receptor functions in morphine-withdrawn subjects (Manzoni and Williams, 1999), chronic morphine
also alters mGlu2/3-mediated events in the NAc. Activation of these receptors induces LTD at NAc glutamatergic
synapses. However, this mGlu2/3-dependent LTD was
abolished during withdrawal from chronic morphine
(Robbe et al., 2002). Together with enhancement of VTA
presynaptic mGlu2/3 function and the ability of mGlu2/3
agonists to reduce morphine withdrawal symptoms,
these findings suggest that regulation of mGlu2/3
synaptic plasticity in the mesolimbic system could
be important for the development of opioid addiction.
Other cellular events underlying chronic opioid
actions in the NAc include trafficking of AMPARs in
the D1R-MSNs. Chronic morphine administration
was associated with a decrease in surface trafficking
of the GluA1 subunit, which could be a substrate of
morphine-induced alterations in neuronal activity
within the NAc (Glass et al., 2008).
The involvement of opioid receptors in the modulation
of hippocampal plasticity has been amply documented.
Chronic opioids produce cognitive deficits in human
opioid users and reduce neurogenesis in the rat HC
(Guerra et al., 1987; Eisch et al., 2000), suggesting that
maladaptive alterations in hippocampal plasticity could
partly contribute to opioid addiction, craving, and relapse. In accordance with this idea, chronic morphine or
heroin treatment attenuated the hippocampal CA1 LTP
during withdrawal and produced deficits in spatial
learning (Pu et al., 2002; Salmanzadeh et al., 2003).
Hippocampal LTP could be restored by re-exposure to
opioids, including the m receptor agonist [D-Ala2, NMePhe4, Gly-ol5]-enkephalin (DAMGO) and inhibitors of
PKA, suggesting that upregulation of the cAMP pathway was one of the underlying mechanisms (Pu et al.,
2002; Bao et al., 2007). In addition, chronic morphine
exposure increased hippocampal extracellular adenosine concentrations, which contributed both to the
inhibition of hippocampal LTP and impairment of
spatial memory retrieval, and both deficits could be
reversed by an adenosine antagonist or adenosine
deaminase (Lu et al., 2010a). There is also evidence to
suggest that opioid-induced changes in hippocampal
synaptic plasticity could have a role in drug-context
associations. Morphine-induced CPP was associated
with increased basal synaptic transmission and impaired hippocampal LTP, accompanied with increased
synaptic expression of the NMDAR subunits GluN1 and
GluN2B. After extinction of CPP, impaired LTP and
elevated GluN2B expression persisted, but morphineprimed reinstatement of CPP was associated with
LTP similar to controls (Portugal et al., 2014). These
findings implicate hippocampal LTP and glutamatergic
transmission in context-dependent morphine effects,

consistent with blockade of morphine CPP by GluN2Bselective antagonists (Ma et al., 2006).
In agreement with the hypothesized role of the
AMPARs in drug-induced plasticity, a 12-hour withdrawal from four escalating morphine doses (5, 8, 10, 15
mg/kg at 12-hour intervals) increased the expression of
GluA2-lacking (Ca2+-permeable) glutamate receptors
(containing GluA1 and/or GluA3 subunits) in mouse
hippocampal synaptic and extrasynaptic fractions, correlating with reduced magnitude of LTD in HC neurons
without changes in sensitivity to AMPA (Billa et al.,
2010). When this same morphine dosing was used in
a specific setting (locomotor activity chambers), the
treated mice challenged with 5 mg/kg morphine 1 week
later showed robust context-dependent locomotor sensitization in the same chambers compared with saline
treatment or unpaired morphine challenge (Xia et al.,
2011). Interestingly, this persistent effect correlated
with increased phosphorylation of GluA1 Ser845 and
impaired LTP in the HC. However, earlier work
revealed that GluA1-KO and GluA1-Arg (Ca2+ impermeable) mutant mice show enhanced context-dependent
sensitization to 3 mg/kg morphine in comparison with
wild-type littermates 5 days after 6-day treatment with
10 mg/kg morphine (Vekovischeva et al., 2001), indicating
that GluA1 subunits are not obligatory for contextdependent morphine sensitization and that their impaired function can be compensated. Indeed, although
a single dose of morphine induces persistent increase in
AMPAR/NMDAR current ratios in VTA DA neurons 24
hours after administration in wild-type mice (Saal et al.,
2003; Heikkinen et al., 2009), it fails to alter this ratio in
GluA1-KO mice that had already increased ratio at the
baseline (Aitta-aho et al., 2012). The lack of the VTA DA
neuron plasticity might correlate with impaired statedependent place preference, because the GluA1-KO failed
to show place preference under morphine testing (Aitta-aho
et al., 2012). Taken together, these data support the role
of the AMPARs in adaptation to opioid effects, although
the details of subunit roles are still poorly known and
most likely differ in different brain regions.
In the mPFC of rats with a history of heroin SA,
GluA2 subunit-containing AMPARs are downregulated
in the principal pyramidal cells, leading to reduced
AMPAR/NMDAR current ratios and increased rectification (Van den Oever et al., 2008), which permitted
heroin seeking in abstinent and extinguished rats by
a compound heroin-related cue. Blocking the GluA2
subunit downregulation (and subsequent LTD?) also
prevented relapse to heroin seeking. Furthermore,
exposure to heroin cues after abstinence almost doubled
the frequency of GABAergic spontaneous IPSCs in
mPFC pyramidal neurons in brain slices prepared 30
minutes after cue exposure (Van den Oever et al., 2010).
The heroin seeking was also associated with a reduction
in ECM proteins around the Pv-containing interneurons, suggesting that the PPN was downregulated to

Drug-Induced Neuroplasticity

enhance the inhibition of principal neurons. These data

indicate that mPFC output is reduced after relapseinducing cue exposure and that relapse to heroin
seeking is associated with altered structural and functional aspects of both glutamatergic and GABAergic
systems in the mPFC.
Drug-induced changes in the structural plasticity of
dendrites are potentially an important component
of synaptic plasticity. Basic research into the dynamics
of the dendritic spines suggests that the size and shape of
individual spines correlates with forms of synaptic
plasticity, such as LTP and LTD at glutamate synapses.
First, stabilization of the transient immature spines
into functional spines is activity dependent. Second,
experimental protocols that induce LTD are linked with
shrinkage or retraction of spines, whereas induction of
LTP enhances formation of new spines and enlargement of existing spines (Nagerl et al., 2004). In sharp
contrast to psychomotor stimulants that increase dendritic branching and density, chronic morphine exposure reduces the size of VTA DA neurons (Sklair-Tavron
et al., 1996; Russo et al., 2007; Mazei-Robison et al.,
2011) and the density of dendritic spines in brain areas
considered relevant for drug addiction, such as the NAc,
OFC, and HC (Robinson and Kolb, 1999b; Robinson
et al., 2002). Because stimulants and opioids similarly
induce transcription factors (e.g., CREB, DFosB) that
regulate expression of cytoskeletal proteins, the disparate findings on spine density are perplexing. It is
possible that stimulants and opioids recruit different
signaling pathways regulating synaptogenesis acting
under CREB or DFosB control or that additional pathways are involved (Russo et al., 2010). For example, the
reduced VTA DA neuron soma size induced by chronic
opioids is hypothesized to be due to downregulation of
BDNF signaling, because it was reversed by local
infusion of BDNF (Sklair-Tavron et al., 1996). Further
downstream neurotrophic signaling pathways mediating this effect include the downregulated Akt-mTORC2
signaling that increases the excitability of VTA DA
neurons and could thereby trigger a compensatory decrease in neuron soma size and DA output (MazeiRobison et al., 2011). The results are consistent with the
view that drug state-associated activity in the brain is
also based on rapid changes in the neuronal structures.
6. Conclusions. Opioids are effective in the acute
treatment of pain, but they are also abused due to their
addictive properties. After chronic exposure, opioids
produce a wide range of neuroadaptations that are
thought to underlie opioid tolerance, withdrawal, and
compulsive use. These adaptations can be identified at
different organizational levels, including those at the m
opioid receptors that undergo desensitization and internationalization, depending on the m opioid receptor
agonist. The alterations in intracellular signaling systems are complex, but opioid-induced upregulation of
the AC-cAMP-PKA cascade in specific synapses in

955

different brain areas is suggested to contribute to

neural and behavioral adaptations associated with
morphine withdrawal. Several neuropeptide systems
have been described to functionally oppose the m opioid
receptor signaling, thus inducing development of opioid
tolerance and dependence. In accordance with the idea
of aberrant forms of synaptic plasticity driving addictive
behavior, opioids influence plasticity both at glutamatergic and GABAergic synapses in many brain regions,
including the mesolimbic DA system. However, further
work is needed to understand how these adaptations
together produce the addicted state of compulsive opioid
use and relapse.
H. Cannabinoids: Multiple Mechanisms and
Possible Indications
Cannabis is one of the oldest and most used illegal
drugs in the world. There are also many potential
therapeutic indications for cannabinoid-based drugs
(Izzo et al., 2009; Pertwee, 2012), with the treatment
of spasticity and pain in multiple sclerosis and of
nausea, lack of appetite, and subsequent wasting in
AIDS having already been translated into clinical
medicine. The importance of normal endocannabinoid
function for brain health was dramatically revealed
during chronic treatment of extreme obesity with
rimonabant, the cannabinoid type 1 (CB1) receptor
inverse agonist. Although rimonabant (SR141716) was
as efficient as any other pharmacological treatment in
producing sustained reduction in weight and normalizing lipid and glucose metabolism in clinical trials
(Despres et al., 2005; Van Gaal et al., 2005), it was
withdrawn from the market rapidly after its launch
because of treatment-associated psychiatric adverse
effects, such as anxiety, depression, and suicidality in
a minority of the population studied (depressed mood
was an exclusion criterium for the clinical studies)
(Christensen et al., 2007; Van Gaal et al., 2008).
Cannabis intoxication is rarely considered lethal for
otherwise healthy subjects (Weissenborn and Nutt,
2012; Hall, 2015). Pediatric cases of cannabis-induced
coma and young- to middle-age adult cases of cannabisinduced cardiovascular fatalities and arrhythmias were
recently reported (Bachs and Morland, 2001; Tormey,
2012; Le Garrec et al., 2014). The low toxicity may be
related to low abundance of CB1 receptors in vital brain
stem nuclei regulating cardiovascular and respiratory
functions (Herkenham et al., 1990), although the receptors are present in the PAG and rostroventral medulla,
in which activation of CB1 receptors may produce
analgesia by disinhibition of descending pain-relieving
neurons (Vaughan et al., 1999, 2000). Another mechanism related to the inherent limits of acute cannabinoid
toxicity may be that treatment with 9-tetrahydrocannabinol (9-THC) activates the ERK1/2-MAPK pathway
via CB1 receptors producing an increase in the cytochrome P450 side-chain-cleavage enzyme (P450scc),

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rapidly increasing the brain synthesis of pregnenolone

from cholesterol (Vallee et al., 2014). Among other
actions, pregnenolone is an allosteric inhibitor of CB1
receptors, thereby significantly reducing a wide range of
pharmacological effects of 9-THC, the main active
substance in cannabis. Moreover, 9-THC is only a partial agonist at cannabinoid receptors (Howlett et al.,
2002), which may limit its toxicity. It should be noted
that synthetic cannabinoids of various chemical structures and receptor binding profiles are much more
potent and efficient than 9-THC, and an alert on their
potential toxicity and lethality recently appeared
(Trecki et al., 2015).
1. Endocannabinoid System as an Endogenous Lipid
Messenger System. The cannabinoid system mediates
its main effects via the CB1 and CB2 receptors (Pertwee
and Ross, 2002; Pertwee et al., 2010). They are modulated by the endocannabinoids (eCB) N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol
(2-AG), plant cannabinoids (phytocannabinoids) such as
9-THC, as well as synthetic cannabinoid agonists {e.g.,
WIN 55,212-2 [R)-(+)-[2,3-dihydro-5-methyl-3-(4morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6yl]-1-naphthalenylmethanone mesylate], CP55,940
[(2)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]trans-4-(3-hydroxypropyl)cyclohexanol], HU-210
[(6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10atetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]
pyran-9-methanol], and JWH-081 [(1-pentyl-1H-indol3-yl)-1-naphthalenylmethanone]} and antagonists (often
inverse agonists) such as the synthetic CB1 receptorselective rimonabant. The CB1 receptor is predominantly
expressed in the brain and plays a role in regulation of
mood and appetite, in processes of pain, in addiction, and
in synaptic plasticity in response to eCB-induced activation (Fig. 12) (for reviews, see Witkin et al., 2005; Katona
et al., 2006; Katona and Freund, 2008; Heifets and
Castillo, 2009; Hoffman and Lupica, 2013). CB2 receptors
are found predominantly in peripheral tissues, such as T
and B cells, keratinocytes, and peripheral nervous system,
and have so far remained a target for preclinical investigations related to immunomodulation (Dhopeshwarkar
and Mackie, 2014; Malfitano et al., 2014).
The cannabinoid system has turned out to be very
complex, because various endogenous and exogenous
ligands are not particularly specific for the cannabinoid
receptors (Pertwee, 2008). For example, the eCB anandamide also targets TRPV1 receptors, cannabidiol targets 5-HT1A receptors, whereas 9-THC, anandamide,
2-AG, and rimonabant all target 5-HT3, glycine, and
GABAA receptor channels. Despite this apparent nonselectivity, the G protein-coupled CB1 and CB2 receptors
mediate most of the cannabis effects, with most behavioral effects of 9-THC being absent in CB1-knockout mice
(Ledent et al., 1999; Zimmer et al., 1999). More recently,
however, CB2 receptors have also been found expressed in
various neuronal populations, as well as in microglia

(Van Sickle et al., 2005). Specifically, CB2 receptors are

present in the VTA DA neurons, and the selective agonists
JWH133 [(6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10atetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran]
and GW405833 [1-(2,3-dichlorobenzoyl)-5-methoxy-2methyl-3-[2-(4-morpholinyl)ethyl]-1H-indole] (antagonized
by AM630) were found to reduce DA neuron firing and
cocaine SA in the wild-type mice but not in CB2 receptor
partial knockout mice (Xi et al., 2011; Zhang et al., 2015a).
Most of the brain CB1 receptors are localized in axons
and presynaptic terminals of GABAergic and glutamatergic neurons (Howlett et al., 2002). This presynaptic
localization is illustrated by the mismatch of CB1
receptor mRNA (enriched in the soma) and the autoradiographic signal for CB1 receptor-specific ligand (e.g.,
[3H]CP55940) in the rodent and human brain. A clear
mismatch is also seen in glutamatergic cerebellar
granule neurons displaying CB1 mRNA in the cerebellar granule cell layer and CB1 ligand binding in the
molecular layer, where the axons impinge on dendritic
trees of Purkinje neurons. Another example is the
mismatch in the GABAergic neurons of the basal
ganglia, showing CB1 mRNA in the caudate-putamen
and presynaptic CB1 ligand binding in the external
segment of the globus pallidus and the substantia nigra
reticulata. Yet the definitive proof for presynaptic
localization of CB1 receptor comes from direct visualization using antibodies at the electron microscopy level
especially in hippocampal GABAergic CCK-expressing
basket cells (Hajos et al., 2000; Katona et al., 2000). In
conclusion, the CB1 receptors are predominantly presynaptic in both glutamate and GABA neurons, and
thus have the possibility to modulate synaptic efficacy
and neuronal circuit functions by controlling the release
of the main neurotransmitters (Freund et al., 2003). As
an example, activation of CB1 receptors on striatopallidal axon terminals leads to presynaptic inhibition of
GABAergic transmission to globus pallidus neurons
(Engler et al., 2006), whereas activation of CB1 receptors on subthalamic neuron axon terminals leads to
presynaptic inhibition of glutamatergic excitation of
globus pallidus neurons (Freiman and Szabo, 2005).
The eCB system is tightly coupled to regulation of
synaptic efficacy. The main eCBs, 2-AG and anandamide,
are formed from membrane phospholipid precursor molecules in the postsynaptic neuron in response to increased
intracellular Ca2+ after intense activation, after which
they are retrogradely released onto presynaptic CB1
receptors (Figs. 2, 6, and 12). The most abundant eCB
2-AG (Mechoulam et al., 1995) is formed from diacylglycerol by the action of specific postsynaptic membraneassociated diacylglycerol lipase (DGLa) (Bisogno et al.,
2003; Matyas et al., 2008), and degraded by presynaptic
monoacylglycerol lipase (MGL) that colocalizes with the
CB1 receptor (Dinh et al., 2002; Gulyas et al., 2004).
Although MGL is responsible for about 85% of 2-AG
hydrolysis, two other serine hydrolase family enzymes

Drug-Induced Neuroplasticity

957

Fig. 12. Endocannabinoids such as 2-arachidonoylglycerol (2-AG) and anandamide (not shown) are synthesized on demand and attenuate excessive
neuronal firing. When a postsynaptic neuron (shown here as a glutamatergic terminal) fires repeatedly, NMDA receptors and voltage-gated Ca2+
channels (VGCC) are activated, leading to influx of Ca2+ and activation of phospholipase Cb (PLCb) and production of diacylglycerol (DAG), which is
subsequently converted to 2-AG by diacylglycerol lipase (DGL). The newly synthesized 2-AG then diffuses to the presynaptically located cannabinoid
CB1 receptor, a Gi protein-coupled receptor that, when activated, deactivates presynaptic VGCCs, leading to an attenuation of neuronal firing and
glutamate release. Finally, the enzymes monoacylglycerol lipase and ABHD6 and 12 hydrolyze 2-AG to arachidonic acid (AA) and other metabolites.

have been discovered with potential roles in hydrolyzing

excess 2-AG, namely postsynaptic ABHD6 and microgliaenriched ABHD12 (Savinainen et al., 2012). Anandamide
(Devane et al., 1992) is synthesized by several enzymes
and degraded by the fatty acid amide hydrolase localized
mainly in the postsynaptic neuron (Gulyas et al., 2004).
Genetic inactivation of DGLa, but not that of DGLb, in
mice abolished retrograde eCB-mediated short-term
synaptic plasticity processes in the cerebellar, hippocampal, and striatal slices using various electrical and
pharmacological ways to induce eCB release (Gao et al.,
2010b; Tanimura et al., 2010).
2. Short-term Plasticity Involving Retrograde Endocannabinoid Signaling. In hippocampal slices, a train
of action potentials of CA1 neurons induces a suppression of GABAA receptor-mediated inhibition (Pitler and
Alger, 1994) with reduced frequency of spontaneous
IPSPs and reduced amplitudes of IPSCs but with
unchanged sensitivity to iontophoretically applied
GABA. This reproducible phenomenon was called DSI
(Fig. 2), and it was further shown that there a was a lag
of about 1 second between the train of action potentials
and maximal DSI and that it was prevented by pertussis toxin (Pitler and Alger, 1994). Therefore, presynaptic mechanisms were hypothesized, and a few years
later, it was found that this transient DSI in pyramidal
neurons was produced by the short-distance retrograde release of eCBs that inhibited GABA release
from interneurons via an action on presynaptic CB1
receptors (Ohno-Shosaku et al., 2001; Wilson and
Nicoll, 2001). Retrograde eCB signaling is very widespread and affects both inhibitory and excitatory synapses. DSE was also observed in the cerebellar cortex,

where a short depolarization of Purkinje neurons

induces the inhibition of glutamatergic inputs from
parallel and climbing fibers (Kreitzer and Regehr,
2001). Similar Purkinje neuron depolarization also
suppresses the GABAergic synapses from cerebellar
cortical interneurons (Tanimura et al., 2010), such as
the GABAergic basket cells (Szabo et al., 2004). In
addition to the HC and cerebellum, DSI and/or DSE is
also observed, e.g., in the VTA DA neurons (Melis et al.,
2004), NAc MSNs (Tanimura et al., 2010; Shonesy et al.,
2013), and in the BLA neurons (Zhu and Lovinger, 2005;
Patel et al., 2009; Yoshida et al., 2011; Shonesy et al.,
2014). Together these findings suggest that the retrograde eCB signaling is a very general local transient
process that tunes neurotransmission (reviewed in
Wilson and Nicoll, 2002; Kano et al., 2009).
Upon firing of a neuron containing the eCB synthesis
machinery, its Ca2+ level increases to micromolar levels
via VGCCs and NMDAR channels, maybe also from
release from intracellular Ca2+ stores (Kano et al.,
2009). Through as yet poorly known mechanisms,
2-AG synthesis is then promoted, part of that being
dependent on the phospholipase PLCb. For a single
activated neuron, diffusion of endocannabinoids
extends to a sphere of about 40 mm (Wilson and Nicoll,
2001), the effect thus remaining very local. Other
important activators of PLCb are all GPCRs that
signal through Gq/11 proteins (Kano et al., 2009), such
as group I mGlu receptors and M1/M3 muscarinic ACh
receptors (Katona and Freund, 2012). The eCB-CB1
receptor system is thus an important part of a versatile mechanism in presynaptic regulation of brain
circuits.

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Signal transduction of CB1 (and CB2) receptors is

mediated via Gi/o proteins (reviewed in Heifets and
Castillo, 2009)). Thus, the activation of CB1 receptors
generally leads to inhibition of AC (leading to reduced
phosphorylation of PKA targets) and P/Q-type calcium
channels and stimulation of inwardly rectifying potassium channels. Many other signaling alternatives have
been proposed for these receptors, which may also be
present as homodimers or heterodimers.
3. Long-term Plasticity and CB1 Receptors. It is
thus clear that the activation of CB1 receptor by
endogenous or exogenous ligands has the potential to
influence synaptic plasticity. An early in vitro study
showed that a low concentration (10 pM) of 9-THC
prolonged LTP, whereas higher concentrations (100 and
1000 pM) reduced the duration of LTP in rat CA1hippocampal slice preparation (Nowicky et al., 1987).
Cannabinoid receptor activation in vitro impairs LTP
and LTD by reducing presynaptic glutamate release to
a level below that what is required to depolarize the
postsynaptic membrane to relieve the Mg2+-blockade of
NMDARs (Misner and Sullivan, 1999). Cannabinoid
receptor agonists (WIN 55,212-2 and CP55,940) and an
antagonist (rimonabant) favor LTD and LTP, respectively, in the glutamatergic synapses of rat PFC slice
preparation (Auclair et al., 2000). WIN 55,212-2 blocks
the induction of LTP and suppresses paired-pulse depression in rat CA1 slice preparation, an effect that is
blocked by rimonabant (Paton et al., 1998). Striatal LTD
at glutamate synapses is produced by postsynaptic release of eCBs, because it is not detected in CB1-KO mice,
it is blocked by rimonabant and activated by postsynaptic
anandamine (Gerdeman et al., 2002). Also, the synthetic
CB1 ligand, JWH-081, impairs LTP in mouse CA1 slice
preparation (Basavarajappa and Subbanna, 2014).
A single administration of 9-THC (3 mg/kg) to mice
blocked the eCB-dependent LTD in the NAc and HC for
at least 1 day and reduced the hippocampal DSI after 20
hours by almost 60% (Mato et al., 2004). A single dose of
9-THC ($5 mg/kg) impairs the LFS-induced LTD in
the HC (Chen et al., 2013b), which is absent in
cyclooxygenase-2 (COX-2) knockout mice. Seven-day
treatment of mice with 9-THC (10 mg/kg) impaired
fear memory (reduced footshock-induced freezing 24
hours after the last dose) and spatial learning and
memory in a water maze test (Chen et al., 2013b). These
CB1 receptor-mediated effects were dependent on increased COX-2 activity and production of PGE2. Furthermore, in the HC, this treatment downregulated the
expression, phosphorylation, and surface trafficking of
GluA1, GluN2A, and GluN2B subunits and consequently reduced LTP at CA3-to-CA1 synapses, which
was apparently correlated with reduced dendritic spine
density of HC-CA1 neurons. Interestingly, 9-THCinduced CB1 receptor activation upregulates COX-2
expression, whereas that by 2-AG suppresses the
COX-2 expression in cell culture models (Chen et al.,

2013b). This suggests that exogenous agonists and

eCBs may have different signaling routes, with
9-THC acting via Gbg subunits and 2-AG via the Gai
subunit. In cultured hippocampal neurons, synaptic
release sites are greatly reduced by incubation with
9-THC, which is mediated by decreased cAMP (Kim
and Thayer, 2001). It should be further noted that the
COX-2 enzyme is known to oxidize eCBs, anandamide
and 2-AG, and to produce derivatives with prostaglandins, the selective inhibition of which has been proposed
to be used in drug development to enhance eCB actions
(Hermanson et al., 2014).
In rats, acute treatment with 9-THC increased ERK,
pCREB, and c-Fos in the caudate-putamen and cerebellum, whereas chronic 9-THC exposure induced
increases in ERK, pCREB, and FosB in the PFC and
HC (Rubino et al., 2004). Blocking ERK activation in
Ras-GRF1-KO mice prevented tolerance to 9-THC in
sedation and analgesia (Rubino et al., 2004). In mice, it
has been reported that a very low dose (0.002 mg/kg) of
9-THC induced long-lasting (7 weeks) modifications of
ERK activity in the HC, FC, and cerebellum and
elevated pCREB in the HC and BDNF in the FC
(Fishbein et al., 2012). The effects of cannabinoids on
the ERK1/2 signaling in vivo were regulated by both D1
and NMDARs (Daigle et al., 2011). Chronic exposure of
rats to 9-THC (1.5 mg/kg for 7 days) upregulated
BDNF in the NAc, posterior VTA, hypothalamic paraventricular nucleus, and mPFC (Butovsky et al., 2005).
Chronic exposure to 9-THC prevents synaptic plasticity in the NAc and reduces sensitivity of GABAergic and
glutamatergic synapses to cannabinoids and opioids
(Hoffman et al., 2003), indicating a possible tolerance
and cross-tolerance development. It is noteworthy that
subchronic treatment of mice with 9-THC induced CB1
receptor desensitization in [35S]GTPgS autoradiography in several brain regions, but not in the striatal
regions, in which the treatment induced the greatest
expression of DFosB (Lazenka et al., 2014). This
suggests that gene expression regulated by DFosB
counteracted the CB1 receptor desensitization.
4. Cannabinoid Effects on Brain Development.
Recent rodent studies have indicated that cannabinoid
exposure to the developing brain during pregnancy or
early development may cause alterations in offspring
behavior and physiology via CB1 receptor-mediated
mechanisms (reviewed in Calvigioni et al., 2014). One
study revealed that maternal exposure to 9-THC affected the stability of cortical neurites and connections
and disrupted CB1 receptor-positive perisomatic baskets
in the cortex (Tortoriello et al., 2014). This was mediated
by a reduction in a microtubule-binding protein Superior
Cervical Ganglion 10 (stathmin-2) via phosphorylation by
CB1 receptor-mediated activation of JNK. Importantly,
reduced expression of Superior Cervical Ganglion
10 mRNA and protein was also found in human hippocampal tissue from cannabis-exposed fetuses (Tortoriello

Drug-Induced Neuroplasticity

et al., 2014). Behavioral effects are also evident, because

CB1 receptor blockade in the prenatal period decreases
immobility behavior, demonstrating that the cannabinoid
system plays a crucial role in ontogeny of psychomotor
behaviors (Moreno et al., 2005).
Cannabinoid receptors in the white matter tracts are
abundant in rats during early brain development but
dramatically reduce by P30 (Romero et al., 1997). In
prenatal brains, WIN55,212 activated [35S]GTPgS
binding in white matter areas, which could be antagonized by the CB1 receptor antagonist rimonabant.
Indeed, various components of the brain eCB system
are present at early development (Fernandez-Ruiz
et al., 2000), suggesting a possible involvement of
cannabinoid signaling in neurogenesis and gliogenesis
(Berghuis et al., 2005; Arevalo-Martin et al., 2007;
Garcia-Ovejero et al., 2013; Zhou et al., 2015), development and myelination of neuronal pathways, and thus
the macro- and microstructure of the brain during
adolescence and adulthood (Keimpema et al., 2011).
Adult neurogenesis in the HC is compromised in DGLaKO and DGLb-KO mice (Gao et al., 2010b), indicating
a role for eCBs. Importantly, CB1 receptors are present
in myelin-forming oligodendrocytes and CB2 receptors
in microglia, with both being increased in white matter
plaques of multiple sclerosis (Benito et al., 2007). As in
rodents, CB1 receptor binding is remarkable in the
white matter tracts of human fetal brains but hardly
detectable in postmortem brains from juvenile or adult
ages (Mato et al., 2003). In heavy cannabis users, axonal
connectivity, as assessed by diffusion-weighted magnetic resonance imaging, was impaired in comparison
with matched controls (Zalesky et al., 2012), with the
impairment correlating with age of starting regular
cannabis use. In another recent study, marijuana use
was associated with reduced gray matter volume of the
OFC and with increased functional and structural
connectivities in the forceps minor pathway (Filbey
et al., 2014). The connectivity changes in the latter
study were associated with early onset of use, being first
increased and then decreased during protracted use.
Thus, longitudinal studies are obviously needed, especially because the reversibility of the changes is not
known. Although the effects of prenatal 9-THC are not
as dramatic as those produced by alcohol abuse during
brain development in pregnancy, it is possible that early
cannabis use could affect brain development during
critical periods and, therefore, be a contributing factor
to later cognitive impairment, substance abuse/
addictions, and symptoms related to mental illnesses.
5. Cannabinoid-Induced Cognitive Impairment.
Cannabis acutely impairs various cognitive, perceptual,
and executive functions (see Ameri, 1999; Iversen,
2000). In one study, memory impairment after acute
cannabis in occasional cannabis users could be counteracted by the acetylcholinesterase inhibitor rivastigmine
(Theunissen et al., 2015), which might also activate the

959

same presynaptic G proteins as 9-THC via indirect

stimulation of mACh receptors. However, similarly to
prolonged use of benzodiazepines that might produce
persistent cognitive impairment, but which has been
hard to prove (c.f., section II.E), the cognitive deficiencies after chronic, heavy cannabis abuse have not been
proven to be persistent (Pope et al., 2002) nor purely
transient (Solowij et al., 2002), although at least one
report showed heavy users still performing worse than
light users after a 4-week abstinence (Bolla et al., 2002).
It should be noted that 9-THC levels remain at
a significant level for a few weeks after stopping the
use of cannabis (Bergamaschi et al., 2013), which could
explain the results of the latter report on cognitive
impairment during the first few abstinent weeks (Bolla
et al., 2002). Although adolescents might be more
sensitive to cognitive impairment by cannabis use, any
persistent impairment is still difficult to assess, and
there appears to be a need for larger longitudinal
studies (James et al., 2013).
Longitudinal studies would also be needed to establish possible gross abnormalities in human brain structural features produced during cannabis/marijuana
use. Some of the recent studies using MRI on subjects
with a history of cannabis use compared with nonusers,
have suggested statistically significant alterations in
gray matter density and/or volumes of brain regions
involved in reward and cognition, such as the HC, NAc,
and amygdala (Yucel et al., 2008; Demirakca et al.,
2011; Gilman et al., 2014; Lorenzetti et al., 2015). Most
recently, the report by Weiland et al. (2015) controlled
for the alcohol use between the daily marijuana user/
nonuser groups by matching the scores on the Alcohol
Use Disorders Identification Test (AUDIT). This study
found no significant effects of marijuana use on gray
matter density and volumes of the bilateral NAc and
amygdala, the HC, and the cerebellum. Although the
cannabis-use associated fine structural alterations cannot be excluded by this result, alcohol use may have
been a significant confounding factor in the earlier
studies in which the groups might have been more
heterogeneous in relation to alcohol use. Even in the
study of Weiland et al., alcohol drinking averaged five
drinks a day in all study groups.
In rats, cannabinoid treatments impair learning and
memory processes, but again the persistence of effects is
not known. Acute pharmacological blockade of MGL,
which increases 2-AG levels, also impairs learning and
memory in rats (Griebel et al., 2015). Chronic 15-day
treatment with a potent cannabinoid receptor agonist
HU-210 (100 mg/kg i.p.) caused impaired learning in
Morris water maze with longer intertrial delays and
reduced LTP in the CA1 region of HC tested 18 hours
after the last dose (Hill et al., 2004). Both 9-THC and
WIN 55,212-2 decrease PFC DA turnover for up to 2
weeks, suggesting that persistent cognitive disturbances after cannabinoid exposure are possible and perhaps

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Korpi et al.

at least partly related to the reduction in the DA

transmission in the PFC (Verrico et al., 2003).
Repeated 9 -THC administration in adolescent
rhesus monkeys impaired age- and practice-related
improvements in accuracy on a spatial working memory
task and neither tolerance nor sensitization developed
to the acute effects after 6 months (Verrico et al., 2014).
This result is consistent with the acute impairment of
cognition by cannabis in adolescent humans.
6. Rewarding and Aversive Behaviors, Specific
Actions on VTA DA Neurons. Cannabis produces
euphoria and also aversive effects, such as anxiety, in
humans. 9-THC induced striatal DA release in
humans in some experiments (Bossong et al., 2009)
but not in others (Barkus et al., 2011). Similarly, in
rodent microdialysis or firing rate studies, 9-THC
induced DA release in some experiments (French,
1997; Tanda et al., 1997) but failed to do so in others
(Castaneda et al., 1991). Importantly, high-resolution in
vivo voltammetric analyses suggest that CB1 receptor
blockade by rimonabant can block DA transients in the
NAc induced by ethanol, nicotine, and cocaine in freely
moving rats (Cheer et al., 2007). Indeed, CB1 receptors
are present in the VTA GABA neurons and in afferent
GABAergic MSNs from the NAc (Matsuda et al., 1993;
Marsicano and Lutz, 1999), which is in keeping with
cannabinoid-induced decrease in GABA release in the
VTA (Szabo et al., 2002). There are no CB1 receptors in
the VTA DA neurons, but they contain the machinery
for eCB synthesis and thus for retrograde signaling.
These results indicate that the CB1 receptor activation
can lead to increased mesolimbic DA release, although
this effect seems to be in several cases more modest than
that induced by other drugs of abuse. Direct infusion of
9-THC to the posterior VTA and the shell of the NAc in
rats induces rewarding behavior, such as lever pressing
for the infusion and CPP (Zangen et al., 2006). Also,
9-THC increases GluA2-lacking AMPA receptors and
causes LTD in the pedunculopontine nucleus, a subcortical nucleus that influences reward and motivational functions (Good and Lupica, 2010). Early studies
on medial forebrain bundle self-stimulation at the
hypothalamus in rats indicated that, like other drugs
of abuse (Wise, 1996), 9-THC also facilitated the ICSS,
especially in Lewis rats (Lepore et al., 1996; Gardner
et al., 1988). However, like the effect on DA release, this
effect of 9-THC has been difficult to replicate in rats or
mice (Vlachou et al., 2007; Fokos and Panagis, 2010;
Wiebelhaus et al., 2015). A recent study with SpragueDawley rats suggested that a lower dose of 0.1 mg/kg of
9-THC reduced the threshold for self-stimulation,
whereas the often-used 1.0 mg/kg failed to do so, both
effects being antagonized by rimonabant (Kwilasz and
Negus, 2012).
There are two important behaviors that appear to be
under the control of eCB system: habit formation by
modulation of dorsolateral striatal neurotransmission

and extinction of aversive memories by modulation of

BLA neurotransmission. Recent development of behavioral assays for goal-directed versus habitual drugseeking behaviors have established specific roles for
the ventromedial striatum in goal-directed behavior
and for the dorsolateral striatum for habitual instrumental responding (Hilario and Costa, 2008; Everitt,
2014;) (Fig. 1). Experiments comparing responses to
immediate rewarding effects versus responding to
devalued rewards, e.g., after a preceding drug or food
reward, have been important to distinguish the goaldirected and habitual instrumental responding
(Balleine and Dickinson, 1998). Repeated responding
for drugs of abuse starts with activation of ventral pathways from the VTA to the NAc, but later overtraining
preferentially activates the dorsolateral nigrostriatal
pathways, previously suggested as a spiraling activation of midbrain-basal ganglia-cortical loops (Haber
et al., 2000; Haber and Knutson, 2010). There exists
a steeply increasing gradient of CB1 receptors from the
medial to lateral striatum (Herkenham et al., 1991),
which correlates with the presynaptic CB1 receptor
actions and retrograde actions of eCBs on striatal
excitatory transmission (Gerdeman and Lovinger,
2001; Gerdeman et al., 2002). Furthermore, pharmacologically isolated EPSCs and IPSCs were found to be
attenuated by neuronal firing-induced eCB release
(Adermark et al., 2009). Thus, both LTD and LTP
processes can be produced in the striatal MSNs by
activity-driven eCB retrograde signaling, which is more
prominent in the dorsolateral than dorsomedial striatum and can promote more habitual than goal-directed
responding. Habit formation is impaired under cannabinoid receptor blockade and in CB1-KO mice (Hilario
et al., 2007). Stimulant drugs initially induce goaldirected drug-seeking behavior, which after overtraining and prolonged drug exposure alters to more habitual
instrumental behavior (Everitt and Robbins, 2005).
This correlates with drug-induced changes in synaptic
functions (LTP, LTD) in the dorsal striatum (Gerdeman
et al., 2003) and possibly agrees with chronic stimulant
treatment-induced changes in the sensitization of behavioral stereotypy and striosomal early gene activation in the lateral striatum (Canales and Graybiel,
2000; Vanderschuren and Everitt, 2005). In THCdependent mice that show no difference in responding
to valued versus devalued rewards, bilateral infusion of
apamin (a SKCa channel blocker) into the dorsolateral
striatum rescued the eCB-dependent LTD (lost during
tolerance development) for up to 5 days and changed the
behavior from habitual responding to goal-directed
responding with a significantly greater responding for
valued than devalued rewards (Nazzaro et al., 2012).
D1R activation (D1R-like) has been linked to LTP and
D2R activation (D2R-like) to LTD in MSN glutamate
synapses (Calabresi et al., 2007). This is correlated with
DA inducing increased NMDAR currents in D1R-MSNs

Drug-Induced Neuroplasticity

and decreased currents in D2R-MSNs (Andre et al.,

2010), with both DA responses being modulated/partly
mediated the eCB system. The role of DA and DA
receptors in MSN plasticity has been restudied using
mouse models with selectively labeled MSNs of the
direct (D1R) or indirect (D2R) pathways (Surmeier et al.,
2009), revealing a complex interplay between timed
firing and dendritic activity and activation of a number
of GPCRs and intracellular signaling cascades (Shen
et al., 2008). In the striatum, CB1 receptors are present
in both direct (striatonigral) and indirect (striatopallidal) MSNs populations (Marsicano and Lutz, 1999;
Hohmann and Herkenham, 2000), presynaptically in
both GABAergic and glutamatergic axon terminals, but
not in TH-positive axon terminals (Fitzgerald et al.,
2012). The differential DA receptor distribution between the direct and indirect GABAergic striatal projection neurons (MSNs) is well known (Gerfen et al.,
1990). D2R activation stimulates anandamide production (Giuffrida et al., 1999), and this DA receptor
subtype has been shown to functionally interact with
CB1 (Kearn et al., 2005) and adenosine A2A receptors
(Ferre et al., 2010). Cocaine decreases striatal GABA
transmission, enhances anandamide synthesis, and
inhibits its breakdown via D2R-like receptor activation
(Centonze et al., 2002, 2004). However, the HFS-eCBdependent LTD at glutamate synapses of striatal MSNs
can be induced by opening of L-type VGCCs (Adermark
and Lovinger, 2007), suggesting that the action of D2R
activation on indirect pathway LTD is not obligatory.
Thus, the effect of D2R activation here is mediated
perhaps via suppression of adenosine A2A receptor
signaling that enhances retrograde eCB signaling (Fuxe
et al., 2007; Lerner et al., 2010). In the direct pathway,
the activation of D1R induces LTP (Calabresi et al.,
2007), after activation PKA-mediated phosphorylation
of DA- and cAMP-regulated phosphoprotein DARPP-32
and other plasticity-related signaling cascades
(Greengard, 2001; Nairn et al., 2004; Svenningsson
et al., 2004). Activation of this cascade has been linked
to the effects of many drugs of abuse (Nairn et al., 2004;
Svenningsson et al., 2004), and some behaviors induced
by 9-THC are altered in DARPP-32 knockout mice
(Lazenka et al., 2015). In line, subchronic 9-THC
selectively induces accumulation of DFosB in D1RMSNs (Lobo et al., 2013). This induction by 9-THC
can be blocked by D1R antagonist, but not by genetic
deletion of DARPP-32 (Lazenka et al., 2015). In conclusion, the present data indicate a central role for CB1
receptors and eCB signaling in the regulation of shortand long-term plasticities in the main striatal projection neuron populations. Further studies will be
needed to better understand the roles of these plasticity
processes in behaving animals.
Cocaine SA in rhesus monkeys was initially associated with reduced [14C]deoxyglucose uptake in the
ventral striatum and PFC, which, after prolonged SA,

961

shifted to the dorsolateral striatum (Porrino et al.,

2004). It is not known whether the cocaine-induced
reduction in striatal activation involves the CB1/2 receptor mechanisms or some other signaling pathways
that are affected by chronic cocaine. In rodents at least,
antagonism of CB1 receptors can abolish the rewarding
effects of cocaine (Xi et al., 2008), whereas the effects of
CB2 receptor blockade may show species differences
between mice and rats (Zhang et al., 2014). The cocaine
SA experiments in rhesus monkeys stress the importance of serial engagement of medial versus lateral
midbrain-striatal-cortical loops. However, these changes
in neuronal activity may be also explained by prolonged
changes in DA release, receptors, and transporters
(Beveridge et al., 2009), not necessarily by eCB-induced
LTD.
Aversive memories induced by drugs might be an
important deterrent of drug abuse. Marsicano et al.
(2002) found that eCB activation promotes extinction of
aversive fear memories by inhibiting GABAergic circuits in the amygdala. By using brain slices, HFS of
lateral amygdala induces LTD of GABAergic transmission in the BLA, which then increased amplitudes of
EPSCs in the neurons of the CeA, the final output nuclei
from the amygdala (Azad et al., 2004). This activation
might then induce a novel memory trace for extinction
of fear conditioning. Notably, CB1-KO animals failed to
show extinction of freezing response to an auditory tone
previously coupled to footshocks. Extinction of appetitively motivated responding was not affected in CB1-KO
animals (Holter et al., 2005). More recently, infusion of
the CB1 receptor antagonist AM251 [N-(piperidin-1-yl)5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1Hpyrazole-3-carboxamide] into the BLA was shown to
abolish the freezing response if infused after the
reactivation of fear memory (Ratano et al., 2014),
suggesting that reconsolidation of fear memory is
dependent on CB1 receptor activation. This effect of
AM251 could in turn be reversed by infusion of
bicuculline, a GABAA receptor antagonist, indicating
that CB1 receptor blockade enhanced GABA transmission. Altogether these results suggest that cannabinoid mechanisms affect the amygdaloid circuitry
and produce long-term alterations in responding to
aversively conditioned stimuli.
7. Cannabinoids during Adolescence: Increased Risk
for Schizophrenia?. Older literature on cannabis
abundantly recognizes that heavy use is associated
with sensory modality alterations and hallucinations
(Iversen, 2000). However, an association between cannabis use and the development of schizophrenia has
been more difficult to demonstrate. A study following
Swedish conscripts from adolescence found a relationship between cannabis use and subsequent development of schizophrenia, with an odds ratio (OR) of about
6 when cannabis had been used chronically more than
50 times (Zammit et al., 2002). This hints toward severe

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Korpi et al.

persistent alterations in brain functions due to cannabis

use, even if the risk appears to decline with time in the
original study cohort (Manrique-Garcia et al., 2012),
and it has been calculated that thousands of users
would need to be intervened to prevent one case of
schizophrenia (Hickman et al., 2009). Meta-analyses
have also found increased risk for different mental
illnesses (OR about 1.4) for those who have ever used
cannabis, especially for those with frequent use (OR
about 2) (Moore et al., 2007). Furthermore, a recent
report showed no increase in cases of first-episode
psychosis with a history of milder hash-resin use but
an increased number of cases with a history of using
stronger skunk-like cannabis (Di Forti et al., 2015).
Cannabinoids may provoke greater pharmacological
effects on cognition and other behavioral domains in
schizophrenic patients (DSouza et al., 2005). Indeed,
a study of young students suggested that individual
variability in propensity to experience psychotomimetic
effects during the first use of cannabis may depend on
polymorphisms of the CB1 gene (CNR1) (and not on
COMT, AKT1, or BDNF polymorphisms) (Krebs et al.,
2014). Although it is possible that cannabis abuse may
accelerate the start of psychosis and schizophrenia in
susceptible individuals, a causal role of cannabis use in
the development of schizophrenia is not established.
Several studies have assessed the effects of cannabinoid exposure on adolescent rodents (reviewed in
Renard et al., 2014). Adolescent female rats treated
(from P35 to P45) with 9-THC develop depressive-like
behavior in adulthood (Rubino et al., 2008, 2009a),
which could be reversed by chronic URB597 (fatty acid
amide hydrolase inhibitor) treatment during adulthood,
indicating a role for eCB-CB1 receptor signaling
(Realini et al., 2011). In rats treated with 9-THC in
adolescence, impaired performance in the radial arm
maze was observed, and this was associated with
decreases in synaptic markers and synaptic efficiency
in the HC and PFC (Rubino et al., 2009a,b). Adolescent
exposure to the CB1 receptor agonist CP 55,940 impaired short-term memory (30- and 120-minute delay)
in a similar fashion in Wistar and Lister Hooded rats.
However, in an object location task, the impairment in
Wistar rats was observed after 30-minute delay but only
after a 120-minute delay in Lister Hooded rats (Renard
et al., 2013). Although the deficits induced by the potent
synthetic cannabinoid agonist HU 210 in learning and
motor activity were reversed in 3 days of abstinence, it
produced more persistent disruption of acquisition and
vocalization that was still evident after a 7-day abstinence (Ferrari et al., 1999). On the contrary, one report
shows that chronic treatment of periadolescent rats
with the cannabinoid agonist CP 55,940 had only
marginal effects on cognition and anxiety during
adulthood with the exception of an elevated hippocampal PSA-NCAM expression (Higuera-Matas et al.,
2009). Taken together, cannabinoid exposure during

adolescence may cause long-lasting effects on behavior,

especially in female rats. Importantly, the experiments
by Schneider and Koch (2003) indicate that the time of
cannabinoid treatment is crucial. Chronic WIN 55,2122 treatment during puberty (from P40 to P65), but not
during prepubertal or adult age, induced prolonged
effects on sensorimotor gating (loss of prepulse inhibition of acoustic startle, which could be normalized by
acute haloperidol 0.1 mg/kg), object recognition memory, and a progressive ratio task in adulthood (P75
P120). Thus, as in humans, the significance of the
timing of cannabinoid exposure for persistent effects is
important (Schneider, 2008), which may be related to
the increased activity of the brain cannabinoid system
during adolescence in humans and experimental animals (Mato et al., 2003; Rodriguez de Fonseca et al.,
1993).
8. Conclusions. Cannabis is a relatively safe drug,
with low potential for lethality in cannibis intoxications
of young people. But because the endocannabinoid
system is wired into mechanisms of brain development
and synaptic plasticity, they have the potential for
producing long-term changes in the nervous system
structure and function. Particularly the heavy cannabis
exposure during adolescence may induce early psychosis and other changes in cognitive and emotional
behaviors. Furthermore, more longitudinal research
is needed for several aspects of cannabinoid-induced
long-term alterations in brain structure and function,
especially with an advent of more potent synthetic
cannabinoids and their entering the illegal markets.
I. Hallucinogens
The study of the persistent effects of 5-HT, lysergic
acid diethylamide (LSD), and other serotonergic hallucinogens on perception, cognition, and mood started more
than four decades ago but has long been hampered by
legislative hurdles (Geyer and Vollenweider, 2008; Nutt
et al., 2013). Therefore, it is only recently that proper
guidelines for psychedelic drug research have been
established (Johnson et al., 2008) and studies have begun
to produce some understanding of the neurochemical
events directly responsible for producing hallucinogeninduced neuroplasticity (Catlow et al., 2013; Lepack
et al., 2015), although many questions still remain.
In this section, the basic pharmacology of hallucinogens is discussed, followed by a review of their acute
effects on neurochemistry and behavior. Finally, the
neuroplasticity of hallucinogens will be discussed in
terms of their long-term effects on sensory processing,
mood, and anxiety.
1. Effects of Serotonergic Hallucinogens Are Mediated
by the 5-HT2A Receptor. The typical serotonergic hallucinogens can be divided into several chemical classes
including tryptamines, phenethylamines, ergolines, and
amphetamines. They all display high affinity for the
5-HT2 receptors but also show varying degrees of affinity

Drug-Induced Neuroplasticity

for a range of other 5-HT receptors including the 5HT1

5HT4, 5HT5, 5HT6, and 5HT7 receptors (Nichols, 2004).
The ergoline hallucinogen LSD, for instance, has the
highest affinity to, and (partial) agonistic effects on,
5-HT2A, 5-HT2C, 5-HT1A, and 5-HT6 receptors in the low
nanomolar range, but also shows intrinsic activity at the
DA D2 and a-adrenergic receptors (Nichols, 2004; Passie
et al., 2008). The tryptamine hallucinogen, psilocybin
(4-phosphoryloxy-N,N-dimethyltryptamine), is synthesized de novo in several species of hallucinogenic mushrooms and, together with its active metabolite psilocin,
it also displays a low nanomolar affinity for 5-HT2A
receptors, and a somewhat lower affinity for 5-HT1A and
5-HT2B receptors (McKenna et al., 1990). With a Ki of
0.7 nM, the 5-HT2A receptor is also the primary target of
the synthetic amphetamine hallucinogen DOI, although
it also targets 5HT2B and 5HT2C receptors with slightly
lower affinities (Canal and Morgan, 2012). Also other
hallucinogens, such as N,N-dimethyltryptamine and
the phenethylamine hallucinogen mescaline have significant affinity mainly to the Gq/11-coupled 5-HT2A/C
receptors (Aghajanian and Marek, 1999; Ray, 2010).
Moreover, efavirenz [(4S)-6-chloro-4-(2-cyclopropylethynyl)4-(trifluoromethyl)-2,4-dihydro-1H,3,1-benoxazin-2-one], a
nonnucleoside reverse-transcriptase inhibitor used for
treatment of HIV-1 infection, shows a risk for neuropsychiatric adverse effects such as night terrors and
hallucinations and is a potent 5-HT2A agonist (Gatch
et al., 2013). MDMA, however, a stimulant with secondary hallucinogenic properties, produces its hallucinogenic effects mainly indirectly, by increasing synaptic
5-HT levels through SERT-mediated 5-HT release
(Liechti et al., 2000).
Although hallucinogens have a number of 5-HT
receptor targets, the hallucinogenic effects in fact
appear to be mediated primarily by one receptor subtype (Fig. 13). The hallucinogen-induced head shaking
response can be restored in transgenic mice lacking the
5-HT2A receptor by selectively restoring this receptor in
cortical pyramidal neurons (Gonzalez-Maeso et al.,
2007), although the discriminative stimulus properties
of LSD and subjective effects of hallucinogens can be
fully blocked by 5-HT2A antagonists in both experimental animals and humans (Vollenweider et al., 1998;
Gresch et al., 2007). Furthermore, the 5-HT2A/C antagonist ketanserin blocks the effect of psilocybin on visual
EEG and event-related potentials and on prepulse
inhibition of the acoustic startle in healthy volunteers
(Quednow et al., 2012; Kometer et al., 2013). This
indicates that the hallucinogenic effects of serotonergic
hallucinogens are primarily mediated by the 5-HT2A
receptor. This receptor subtype is enriched in the deeper
cortical layers (Andrade, 2011).
Aside from serotonergic hallucinogens, other drugs
that produce hallucinogenic effects include substances
such as ketamine, nitrous oxide, and phencyclidine,
which belong to a subtype of hallucinogens often

963

referred to as dissociatives, acting primarily as NMDAR

antagonists. In recent years, a number of new analogs,
such as methoxetamine and 3-MeO-PCP have become
available on the recreational drug market. They have
been shown to have a similar mechanism of action
(Morris and Wallach, 2014; Roth et al., 2013). Additionally, drugs such as dextromethorphan and salvinorin A
that act primarily as m-, d- or k-opioid receptor agonists
or as monoamine reuptake inhibitors, are also included
in the class of dissociative hallucinogens (Codd et al.,
1995; Burns and Boyer, 2013; Morris and Wallach,
2014). So, although the 5-HT2A receptor is the most
important for mediating the hallucinogenic effects of
serotonergic hallucinogens, many other receptors mediate the hallucinogenic effects of other classes of
psychedelics. As the receptor targets of serotonergic
hallucinogens have been clearly identified, it raises the
question of what downstream affects result after modulation of receptor activity by these substances.
2. Hallucinogen ActionA Perturbation of Sensory
Gating or Desynchronization of Cortical Rhythms?.
The involvement of 5-HT2A receptors in the apical
dendrites of cortical pyramidal neurons in producing
hallucinogenic effects (Gonzalez-Maeso et al., 2007)
suggests involvement of cortical circuit mechanisms.
Evidence of thalamocortical glutamate pathway involvement comes from a study demonstrating hallucinogeninduced changes in glutamate release (Aghajanian and
Marek, 1999). These results were supported by human
imaging studies performed in subjects under acute
exposure to hallucinogens (psilocybin, mescaline, and
ketamine) that indicate activation of the frontal, cingulate, and insular cortices, with reduced activation in
the striatum, thalamus, and parietal cortex (Geyer and
Vollenweider, 2008). Interestingly, a more recent experiment using intravenous psilocybin (2 mg) indicated
reduced blood flow and blood oxygen level signals in
the anterior and posterior cingulate cortex and thalamus
of psilocybin-experienced healthy volunteers reporting
strong subjective acute effects of the drug (CarhartHarris et al., 2012). This was replicated by a subsequent
magnetoencephalography study showing large decreases
in spontaneous oscillary power after psilocybin, especially in cortical association areas and default-mode
network (Muthukumaraswamy et al., 2013). These
changes were of neuronal origin, consistent with excitation of 5-HT2A receptors on deep layer 5 pyramidal
neurons, which results in activation of inhibitory mechanisms in more superficial layers (Andrade, 2011;
Bastos et al., 2012).
The sensory gating theory of hallucinogenic action
states that hallucinations occur because of drug-induced
perturbations of the limbic cortico-striato-thalamiccortical feedback loop and subsequent reduction of thalamic sensory gating, leading to sensory overload that
manifests as hallucinations (Vollenweider, 2001). The
action of other drugs capable of inducing hallucinations,

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Korpi et al.

such as NMDAR antagonists and even amphetamine,

may be explained using the same model, suggesting that
alterations of the cortico-striato-thalamic-cortical loops
may be a final common pathway for all hallucinogenic
drugs. Moreover, the drug-induced hallucinatory state
also shows strong phenomenological similarity to acute
psychosis in patients suffering from schizophrenia, and
both states are reversed by antipsychotic drugs, which
has led to use of the hallucinogen-induced state as
a pharmacological model of psychosis (Vollenweider et al.,
1997a,b). More recently, however, the cortical desyncronization theory of hallucinogen action (see the previous
paragraph) has replaced the sensory gating theory,
because the drug effects can be explained by direct actions
on cortical 5-HT2A receptors. Moreover, pharmacological
models of psychosis can be induced by many drugs
activating or inhibiting the main cortical neurotransmitter systems (reviewed in Steeds et al., 2015).

Fig. 13. The hallucinogenic effects of serotonergic hallucinogens such as

mescaline (MESC), psilocybin (PSILO), LSD, and DOI are primarily
mediated by the 5-HT2A receptor. However, most hallucinogens also show
affinity for a variety of other 5-HT receptors, including both postsynaptic
receptors as well as presynaptic inhibitory autoreceptors. Drugs such as
MDMA and related substances, such as methylone, are not primarily
hallucinogens but do produce some hallucinogen-like effects in users.
These effects are not primarily due to direct interaction with the 5-HT2A
receptor but are instead mediated predominantly due to the fact that
MDMA enhances synaptic serotonin levels through competitive reuptake
inhibition and enhancement of 5-HT release. The downstream effects of
5-HT receptor stimulation include activation of phospholipase C (PLC),
adenylate cyclase (AC), and subsequent modulations of postsynaptic
diacylglycerol (DAG), inositol trisphosphate (IP3), and cyclic adenosine
monophosphate (cAMP) levels.

3. Behavioral Effects and Addiction Potential.

Serotonergic hallucinogens, and also some other hallucinogens such as salvinorin A, do not have any clear
rewarding potential in animal models (Passie et al., 2002;
Nichols, 2004; Cunningham et al., 2011). Similarly, although these substances are used frequently by humans,
addiction appears to be very uncommon, and indeed they
have been used to treat alcohol addiction (Gable, 1993;
Studerus et al., 2011; van Amsterdam et al., 2011; Krebs
and Johansen, 2013). This is consistent with the rather
low-affinity, mixed and delayed efficacy of LSD on various
types of DA receptors (Passie et al., 2008); with a very low
affinity of psilocybin/psilocin to DA receptors (Passie et al.,
2002) and with salvinorin A having selective high affinity
to and agonistic efficacy on k-opioid receptors (Roth et al.,
2002; Chavkin et al., 2004). Although the k-opioid receptor
agonists may also influence DAergic mechanisms, they are
generally aversive (decreasing DA release) and in fact
produce conditioned place aversion (Gable, 1993; Zhang
et al., 2005; Cunningham et al., 2011). Interestingly, dosedependent rewarding/aversive effects in place conditioning
with salvinorin A via k-opioid and CB1 receptors have been
reported in zebrafish (Braida et al., 2007).
On the other hand, a 3-month LSD treatment of rats
(0.16 mg/kg i.p. every 2nd day) induced hyperlocomotion
for at least 3 months after discontinuation of the
treatment (Marona-Lewicka et al., 2011), which suggests an action on DA receptors. Indeed, using a drug
discrimination paradigm, Marona-Lewicka and coworkers showed that LSD produces initial generalization
to a 5-HT2A agonist (and suppression of locomotion),
followed at a later phase of cue responding, and
generalization to a D2 agonist (and locomotor activation) (Marona-Lewicka et al., 2005; Marona-Lewicka
and Nichols, 2007). The prolonged LSD treatment
shows development of persistent psychosis-like behavioral and neurochemical features in rats (MaronaLewicka et al., 2011), with at least the hyperlocomotion
being antagonized by antipsychotic drugs blocking D2
and/or 5-HT2A receptors.
The picture is somewhat different with regard to
NMDAR antagonism-based psychedelics, because there
is some evidence that dissociative psychedelics such as
ketamine and PCP are self-administered, at least under
some circumstances (Broadbear et al., 2004; Carroll
et al., 2005; De Luca and Badiani, 2011). These effects
are likely related to the ability of these substances to
increase accumbal DA release and turnover (Carboni
et al., 1989; Irifune et al., 1991) (see section II.F).
4. Long-term Residual Effects of Serotonergic Hallucinogens: the Role of Neuroplasticity. Hallucinogens produce clear neurochemical and acute behavioral and
subjective effects. However, they also produce more
long-term, persistent effects on behavior and sensory
processing, as well as on mood and attitude.
a. Sensory processing. Hallucinogen-induced longterm alterations of sensory processing have been

Drug-Induced Neuroplasticity

reported, initially as LSD-like recurrences or "flashbacks" in the 1950s. Later, diagnostic criteria were
proposed for flashbacks in the DSM-III-R that were
further refined and termed hallucinogen persisting
perception disorder (HPPD) in the DSM-IV (American
Psychiatric Association, 1994). Although this disorder
has a very low prevalence (Halpern and Pope, 2003),
HPPD is characterized by perceptual symptoms, most
often visual in nature, that manifest themselves in
patients previously intoxicated with hallucinogens,
even long after the cessation of drug intake (and beyond
the accepted time of the drugs acute pharmacological
actions), associated with significant distress, and without being attributed to any other medical condition or
psychiatric disorder (Horowitz, 1969; Abraham et al.,
1996; Halpern and Pope, 2003). Several discrete case
studies report flashback phenomenon days to months
after the use of hallucinogens such as LSD (Duncan,
1974) and psilocybin (Espiard et al., 2005) alone or in
combination with alcohol or other drugs of abuse, but
there are hardly any controlled studies on the subject. It
is noteworthy that pharmacological treatment, e.g.,
with antipsychotics, benzodiazepines, and clonidine,
has proved useful in controlling the symptoms in most
of the few cases published (Halpern and Pope, 2003).
Alterations in visual processing may be better described without reference to HPPD, because this diagnosis requires the presence of significant distress
associated with the symptoms. Persistent effects such
as perception disorders have also been observed in
healthy individuals after experimentally administered
doses of psilocybin (Studerus et al., 2011), and these
could all be managed by interpersonal discussion and
support. Furthermore, drug-free visual experiences
were observed in 62% of the respondents in a webbased study that analyzed a population of 2455
participants for abnormal experiences associated with
a history of hallucinogen use, especially LSD (Baggott
et al., 2011). The persistent perceptual alterations in
subjects with past hallucinogen use is clear evidence of
neuroplasticity. Even in the absence of recent LSD use,
patients with HPPD display an augmented neural
coherence in the occipital regions (isolated from anterior
regions) that is proposed to underlie their illusions and
hallucinations (Abraham and Duffy, 2001). However,
little is known about the exact mechanisms responsible
for these changes or about the factors involved in
producing susceptibility to long-lasting sensory alterations or HPPD.
b. Mood and anxiety. It has been known for a long
time that serotonergic hallucinogens can produce longlasting effects on mood, anxiety, and other aspects of
neuropsychiatric functioning, thereby providing indirect evidence of neuroplasticity. For instance, LSD was
studied early on as a drug or an adjunct to other
treatment modalities for neuropsychiatric illnesses,
but research collapsed in the late 1960s after LSD and

965

other psychedelics were made illegal. Subsequently,

a long period largely devoid of any psychedelic research
followed, something that has been attributed largely to
the fact that their illegality made it excessively difficult
for researchers to work with these substances (Nutt
et al., 2013). However, after a long hiatus, there now
appears to be a renewed interest in the potential clinical
applications of psychedelic drugs, such as psilocybin
and LSD and also other psychedelic drugs including
ketamine and MDMA, for treating disorders ranging
from alcohol and nicotine addiction to depression,
anxiety disorders, and cluster headaches (Sewell
et al., 2006; Chabrol, 2013; Grob et al., 2011; Krebs
and Johansen, 2012; Mithoefer et al., 2013; Gasser
et al., 2014; Moaddel et al., 2015). Evidence of longterm effects on behavior comes also from a set of studies
where psilocybin was administered to healthy subjects.
They reported that doses of psilocybin that resulted in
strong visual and perceptual effects, including those
described as mystical-type experiences, subsequently
also produced persistent positive changes in mood,
attitude, and behavior that were sustained for more
than 1 year after the drug was administered (Griffiths
et al., 2006, 2011; MacLean et al., 2011). This suggests
that serotonergic hallucinogens may possess anxiolytic,
antiaddictive, and antidepressive properties, but the
question remains what mechanisms mediate the neuroplasticity required to produce these long-lasting effects.
One recent study attempted to shed light on the
relationship between the therapeutic effects of serotonergic hallucinogens and their effect of neuroplasticity by measuring the effects of varying doses of
psilocybin on extinction of fear conditioning and neurogenesis in mice (Catlow et al., 2013). They demonstrated that psilocybin significantly accelerated the
extinction of fear conditioning, and this was associated
with a trend toward increased neurogenesis in the
dentate gyrus. Although further work is needed, one
could speculate that the effects of psilocybin on neurogenesis are due to 5HT2A receptor-mediated upregulation of BDNF (Vaidya et al., 1997), suggesting a mechanism
strongly resembling that of SSRIs (Martinowich and Lu,
2008; Catlow et al., 2013; Quesseveur et al., 2013) and
possibly the antidepressive mechanism of ketamine
(Lepack et al., 2015).
Considering the vital role of the 5HT2A receptor, it is
important to note that although the 5-HT2A receptor is
the primary target for hallucinogens, there are other
5-HT2A agonists, such as lisuride, that do not produce
any hallucinogenic effects. The exact reason for this
difference is not known, but may be related to differing
recruitment of intracellular second messengers; although both LSD and lisuride activate PLC, only LSD
also recruits Gi/o proteins and Src (Gonzalez-Maeso
et al., 2007). Interestingly, the specific 5HT2A receptor
activation caused by hallucinogens seems to be of key
importance in producing neuroplasticity. Hallucinogens

966

Korpi et al.

such as LSD induce brain-region dependent mRNA

expression of various immediate early genes, such as
c-Fos, arc, and homer1a splice isoform ania3 (Nichols
and Sanders-Bush, 2002), that influence regulation of
gene expression and synaptic responses, whereas DOI
has been shown to produce changes in dendritic spine
morphology on cortical neurons (Jones et al., 2009).
Chronic LSD administration to rats causes a persistent
increase in synthesis and turnover of 5-HT as well as
downregulation of cortical 5HT2A receptors (Diaz and
Huttunen, 1971; Lee and Geyer, 1980; Gresch et al.,
2005), and a 2-week LSD treatment followed by 14 days
of abstinence still showed an augmented 5-HT level in
the midbrain and cerebral cortex (Peters and Tang,
1977). Continuous delivery, but not daily injections, of
LSD in rats caused long-lasting increases (measured
after 30 days) in [3H]LSD binding in the FC, amygdala,
septum, and NAc that coincided with behavioral alterations (King and Ellison, 1989). LSD (1 mg/kg) causes
a sustained increase in Nor1 gene expression in the
PFC, which could play a role in synaptic dysregulation
(Nichols et al., 2003). Similar effects of LSD and DOI on
transcriptional responses in mouse somatosensory cortex
were dependent on 5-HT2A receptors, because they were
absent in 5-HT2A-KO mice (Gonzalez-Maeso et al., 2003).
Importantly, lisuride, a 5-HT2A agonist not producing the
hallucinogenic activity-correlating head-twitching behavior in rodents, failed to produce similar transcriptomics
changes as LSD and DOI. These results are consistent
with 5-HT2A receptor antagonists abolishing the behavioral effects of hallucinogenic drugs (Fiorella et al., 1995;
Vollenweider, 1998; Winter et al., 1999).
5. Scopolamine: Another Hallucinogen Revisited for
Depression. Scopolamine (hyoscine or burundanga) is
a nonselective muscarinic antagonist well known for its
use in preclinical animal models to induce cognitive
impairment and for its use to treat, e.g., motion
sickness. Scopolamine disrupts working memory and
other parameters in rodents, canines, and primates
(Rupniak et al., 1989; Araujo et al., 2004; Winsauer
et al., 2004; Klinkenberg and Blokland, 2010). Some
case reports have revealed hallucinogenic effects of
scopolamine, largely from patients of different age
groups in whom hallucinations unexpectedly followed
peripheral administrations (transdermal patch or
eye drops) of scopolamine (Warburton et al., 1985;
Sennhauser and Schwarz, 1986). A sparse amount of
literature predicts that scopolamine could be addictive
and it is likely to cause CNS effects upon withdrawal
(Luetje and Wooten, 1996; Patel and Ezzo, 2009), but its
recreational or predatory use has not been convincingly
identified (King et al., 2014). On the other hand,
scopolamine might have a beneficial effect in opioid
and cocaine addiction (Gambelunghe et al., 2014; Liu
et al., 2013). With the recent interest in exploration for
quick-onset antidepressants, scopolamine, like ketamine, was reported to be a prospective candidate and

interestingly the clinical improvement lasted for more

than 2 weeks (Furey and Drevets, 2006). These reports
show that although the cognitive impairments are due
to mAChR antagonism, the persistent effects of scopolamine that might be mediated via NMDAR gene
expression and mTOR signaling-mediated synaptic
plasticity (Drevets et al., 2013); these ideas need to be
investigated in the future.
6. Conclusions. The hallucinogenic effects of serotonergic hallucinogens are mediated primarily by the
5HT2A receptor, activation of which produces hallucinations by a range of functional changes thought to
result in deficient thalamic sensory gating and/or
cortical desyncronization. Furthermore, 5HT2A receptor
activation by hallucinogens also mediates many
changes in gene expression, receptor regulation, and
synaptic morphology likely to be associated with the
long-term, persistent effects of hallucinogens on perception, mood, and anxiety. However, the molecular
mechanisms linking the neuropharmacological actions,
human brain functional changes, and behavioral outcomes need to be further studied.
III. General Discussion
We have reviewed neuroplasticity induced by cocaine,
amphetamine, and related psychostimulants, nicotine,
ethanol, benzodiazepines and other GABA ligands,
NMDAR antagonists, opioids, cannabinoids, and hallucinogens. Brain regions implicated across the various
classes of drugs of abuse were diverse but again certain
commonalities emerged. As might be expected, the VTA
was recurrently implicated, but other brain regions that
featured repeatedly across classes of drug of abuse were
the striatum, amygdala, BNST, Hb, mPFC, and HC.
Although there are many diverse mechanisms of neuroplasticity specific to the pharmacology of each of these
classes of drug of abuse, many common themes
surfaced.
Among the drugs of abuse that might be characterized as having stimulant and/or disinhibitory effects
cocaine, amphetamine and related psychostimulants,
nicotine and ethanol, and benzodiazepinesa recurrent
theme was the role of neuroplasticity of glutamate
synapses in the VTA DA neurons. However, the specific
mechanisms of early induction of the persistent changes
in the AMPAR/NMDAR ratios varied between the
different drugs. Additional investigations are required
to further elucidate whether different drugs induce
glutamate neuroplasticity in different populations of
VTA DA neurons, perhaps one of them linking to
reinforcing mechanisms and another one to aversive
mechanisms.
Another commonality was the recurrent role of
GABAergic mechanisms, by disinhibition of the DA
neurons, in the VTA in the neuroplasticity induced by
cocaine, nicotine, ethanol, benzodiazepines and other

Drug-Induced Neuroplasticity

GABA ligands, opioids, and cannabinoids. The specific

mechanisms of induction of changes in GABAergic
function in the VTA varied between the various classes
of drugs, and further studies are required to investigate
whether there would be possibilities in controlling
GABAergic function at specific neuronal populations
in the midbrain to modulate addictive behaviors across
these different classes of drugs.
An overarching theme that has repeatedly emerged is
concern over the possibility that neuroplasticity induced by one drug of abuse may increase the risk of
dependence on other drugs of abuse. In particular, there
is concern that relatively easily available drugs of abuse
such as nicotine and alcohol may trigger mechanism of
neuroplasticity that predispose to increased risk of
abuse of other drugs. However, further studies are
required to determine whether the underlying mechanisms of neuroplasticity induced by nicotine and alcohol
predispose risk to addiction to all other drugs of abuse
equally or preferentially to specific classes of drug of
abuse. Moreover, the question of the reversibility of the
neuroplastic changes induced has seldom been exhaustively addressed. For many of the drugs of abuse the
question of whether there is long-lasting and irreversible alteration of function has not been fully resolved.
Further studies are required to determine how long
these changes continue to increase the risk of drug
abuse.
Another overarching theme that has repeatedly
emerged across our discussion of the various classes of
drugs of abuse is the particular vulnerability of the
adolescent brain to drug-induced neuroplasticity. Evidence is accumulating for concern over significantly
stronger and more insidious induction of plasticity on
adolescent drug exposure compared with adult drug
exposure. Adolescent exposure to drugs of abuse is
a major concern because the relatively easy availability
of alcohol, nicotine, and cannabis in many societies
could lead to risk of exposure. Even limited exposure
may be sufficient to induce neuroplastic changes in the
highly sensitive adolescent brain, leading to increased
risk of later life addiction not only to nicotine and alcohol
but also to other drugs of abuse (Table 3). The adolescent/
early adulthood period in rodents is also sensitive to
nondrug interventions, such as effects of environmental
enrichment (reviewed in Nithianantharajah and
Hannan, 2006).
A. Novel Methods for Future Studies
Further investigations of the mechanisms of action
and persistent neuroplasticity induced by drugs of
abuse are clearly warranted. Recent methodological
advances in systems neurobiology may provide new
tools for such investigations. In the past decade or so,
a variety of techniques with unprecedented resolution
has been developed. Research on long-term neuroplasticity in addiction can benefit tremendously from the

967

continued use of these techniques and incorporation of

others. In this regard, advances in optical techniques
have enabled us to manipulate the activity of certain
classes of neurons and determine their causal role in
brain function. As such manipulations (e.g., optogenetics) have high temporal resolution, their effect on the
firing characteristics of neurons, using optical and
electrical readouts, can be simultaneously monitored
along with their effect on behavior. This has allowed us
to observe how changes in behavior correlate with
changes in the "neural code" (the firing pattern of
populations of neurons).
Closed-loop optogenetics (i.e., optical stimulation of
the brain when a certain criteria is met, e.g., on or before
SA or when a certain pattern of activity is observed in
the brain) are helping us further understand addiction.
Indeed, it is conceivable that in the future we might be
able to manipulate, using optogenetics and chemogenetics, increasingly more specific classes of neurons
(e.g., only the projections from and to certain regions in
the brain that selectively express three or more genes).
Furthermore, recent developments in optogenetic technologies including red-shifted opsins (Chuong et al.,
2014) will enable simultaneous optogenetic stimulation
of two genetically distinct cell types or projections and
hence, elucidate the causal role of different populations
of neurons with unprecedented temporal precision (e.g.,
the behavioral effects of simultaneous manipulation of
D2R- and D1R-MSNs). Additionally, direct optical control of intracellular pathways (reviewed in Stuber and
Mason, 2013) can provide an understanding of the
role of specific intracellular signaling pathways in
a specific population of neurons with similar temporal
resolution. At the other end of the spectrum, optofMRI,
which involves the combination of optogenetics and
fMRI, can elucidate changes in functional connectivity
at the level of the brain (Lee, 2011). Similarly, recent
advances in optical imaging techniques, including development of genetically encoded calcium indicators (for
instance, Gcamp6; Chen et al., 2013c) with the necessary temporal resolution to detect action potentialassociated calcium ion changes and suprathreshold
subcellular activity and development of red-shifted
genetically encoded calcium indicators (Rcamp;
Akerboom et al., 2013), will soon enable simultaneous
optical imaging from different populations of neurons in
vivo (using implantable imaging devices, albeit at
a lower resolution) or ex vivo (similar to the ex vivo
brain slice patch-clamping techniques currently in
widespread use but allowing the visualization of
multiple neurons simultaneously) (see Deisseroth and
Schnitzer, 2013).
Monitoring calcium ion dynamics associated with
neuronal activity is advantageous, because calcium ions
play a fundamental role in induction of synaptic plasticity
and hence, possibly in the long-term neuroplasticity
induced by drugs of abuse. On the other hand, recent

968

Korpi et al.
TABLE 3
Examples of the long-term effects of postnatal/adolescent drug exposures on the brain and behavior in adulthood

Drug/ Intervention

Alcohol
Nicotine

Period

Effects in Adulthood

P2545
P3043
P3648
P3443

Increased social anxiety

Increased alcohol drinking
Disruption of locomotor habituation
Increase in nicotine intake, disturbed
attentional behavior, increased impulsiveness
Decreases reward sensitivity, increased stress
sensitivity, vulnerability to depression
Increased stimulant effects of cocaine,
abnormal shift in attention, decreased
anxiety, deficient contextual fear response
Increased locomotor response to morphine
Increased reinstatement of morphine CPP
Reduced social interaction and novel object recognition
Increased heroin SA
Impaired cognitive behavior, model for psychosis
Reduced exploration, normal social interaction
A great number of neuroplasticity changes in
neuropsychiatric animal models

P30-44
Cocaine
Morphine
-THC
9

Phencyclidine
Environmental
enrichment

P3546
P3032
P3742
P3051
P2849
P515
P3542
Prolonged, at
variable times
after weaning
P6096
P3060

Multiple structural and gene expression

changes in the brain
Transient decrease in cocaine seeking

advancements in genetically encoded voltage indicators

enable the simultaneous detection of voltage fluctuations
in multiple neurons and combined with optogenetics
enable "opto-patching" of neurons ex vivo, if not in vivo
yet (Hochbaum et al., 2014). These advancements can
greatly benefit the drug research and addiction fields
because ex vivo techniques have been very successfully
used thus far.
Similarly, the burgeoning field of chemogenetics
provides the opportunity to specifically modulate (via
GPCRs or ion channels) a certain genetically defined
and/or spatially defined population of neurons using
systemic administration of synthetic ligands, which do
not affect other neurons. This provides the advantage
over optogenetics of performing noninvasive chronic
interventions even across spatially nonrestricted population of neurons (for instance, D2R-expressing neurons across the brain) and possibly simultaneous
activation or inhibition of multiple pathways across
the brain (see Sternson and Roth, 2014).
Furthermore, optrodes with high-density silicon
microelectrodes coupled with multiple microoptogenetic stimulation points (for optical tagging and
stimulation of small regions) allow chronic acquisition
of neuronal activity from large-scale "identified" neuronal ensembles. In addition, novel techniques have been
developed to allow visualization of receptor expression
and the anatomic pathways in unprecedented detail
without sectioning the brain (e.g., Hama et al., 2011;
Chung and Deisseroth, 2013). These techniques will
allow for an improved visualization of structural and
biochemical changes induced across the brain during
addiction.
Finally, recent development of genome engineering
technologies based on CRISPR-associated RNA-guided
endonuclease Cas9 (CRISPR-Cas9) enable easy editing

Reference

(reviewed in Spear, 2014)

(Adriani et al., 2004)
(Adriani et al., 2003;
Counotte et al., 2011)
(Iniguez et al., 2009)
(Black et al., 2006; Sillivan et al., 2011)
(White and Holtzman, 2005)
(Schwarz and Bilbo, 2013)
(reviewed in Rubino and Parolaro, 2008)
See the section II/F.
(Metaxas et al., 2014)
(reviewed in Nithianantharajah
and Hannan, 2006)
(Mychasiuk et al., 2014)
(Chauvet et al., 2012)

or removal of any DNA sequence within the endogenous

genome at any age. Indeed, multiple CRISPR-Cas9
mediated genetic manipulations can be performed
simultaneously (Hsu et al., 2014). This technique holds
potential to elucidate the roles of different genes,
at different time points, in the development of addiction.
Targeted knockdown of multiple genes will allow us
to determine the role of non-Mendelian genes in addiction. Furthermore, this technique will enable us to
understand the complex interplay of genes in such
disorders, which was not possible with knockdown of
a single gene.
The techniques discussed in this section allow unprecedented access to probe brain form and function.
Therefore, great insights in to the neural mechanisms
underlying addiction can be expected in the years to
come.
Understanding addiction will also require elucidation
of the genetic and epigenetic changes, the alterations
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changes in release of neurotransmitters and receptor
expression levels, systems-level neural processing in
different brain structures and the resultant change in
information processing across structures, and, finally,
understanding how these changes translate into altered
behavior. This is by no means a small feat. The issue is
further complicated by the fact that different drugs
affect the brain differently and the role of each of the
aforementioned factors changes as the disease progresses. One of the principal goals of addiction research
is to understand and develop therapies for addiction by
finding commonalities and differences between various
drugs of abuse. Our review of neuroplasticity induced by
cocaine, amphetamine, and related psychostimulants,
nicotine, ethanol, benzodiazepines and other GABA

Drug-Induced Neuroplasticity

ligands, NMDAR antagonists, opioids, cannabinoids,

and hallucinogens offers a step toward consolidating the
current status of knowledge of such commonalities and
the identification of directions for future research.
Authorship Contributions

Wrote or contributed to the writing of the manuscript: Korpi, den

Hollander, Farooq, Vashchinkina, Rajkumar, Nutt, Hyyti, Dawe.
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