Drugs and Behavior Test 3 Study Guide: -nicotine derived from tobacco plant -cigarette smoking=drug addiction (nicotine

self administration): Chronic use in the face of negative consequences Withdrawal symptoms Animal models IVSA nicotine and show CPP with nicotine. IPI-inter puff interval decreases as dose of nicotine in a cigarette decreases. Low dose of nicotinic receptor antagonist decrease IPI. -nicotine binds to nicotinic acetylcholine receptors and increases dopamine levels in reward pathways (VTA Accumbens) by enhancing glutamate release and inhibiting GABA release in the VTA. -adolescent sensitivity- GABA transmission in the VTA (from VTA neuron to DA releasing neuron from VTA to accumbens) inhibits accumbens DA levels. The opposite is true of glutamate releasing neurons in the VTA (stimulate dopamine release from VTA to accumbens). Adolescent sensitivity to nicotine results from enhanced glutamate and underdeveloped GABA systems. -two types of receptors for acetylcholine (Ach): Nicotinic- ligand gated ion channels Muscarininc- GPCR -Clonginger theory of alcoholism Type 1: over age 25, associated with anxiety, guilt, loss of control over alcohol intake. Type 2: under age 25, associated with impulsivity and antisocial behavior. -alcohol-affects a wide variety of transmitters, main behavioral symptoms result from facilitated GABA transmission. -marijuana: comes from cannabis sativa and cannabis indica plants (differ in psychoactive potency). Antiemetic- helps prevent nausea and vomiting Impairs attention Active ingredient- tetrahydrocannabinol (THC)

-THC- binds to cannabinoid receptors, CB1 and CB2 (bound by anandimide and other endocannabinoids produced by the body). THC functions as a partial agonist (activates receptor but not to its full potential).

-Endocannabinoids are released by a depolarized neuron and bind to CB1 receptors on the presynaptic neuron, inhibiting GABA release or glutamate release depending on the neuron. Schizophrenia: -floridly schizophrenic- excessively or dramatically schizophrenic. -DSM IV- two or more of the following for most of 1 month: Delusions Hallucinations Disorganized speech Grossly disorganized or catatonic behavior Negative symptoms: e.g., affective flattening (diminished emotional expressiveness), social withdrawal (Only 1 criterion needed if delusions are bizarre or there is a voice keeping up a running commentary). -schizotypal- personality disorder that is characterized by a need for social isolation, anxiety in social situations, odd behavior and thinking, and often unconventional beliefs. -Schizoaffective disorder- a mental disorder characterized by recurring episodes of elevated or depressed mood, or of simultaneously elevated and depressed mood, that alternate with, or occur together with, distortions in perception. -Introduction of Chlorpromazine (Thorazine) was responsible for the decline in inpatient mental hospital residents. -There is a genetic basis for schizophrenia although not 100% (monozygotic twins are not both schizophrenic if one is). Associated with enlarged cerebral ventricles. -Side effects of antipsychotics: motor extra pyramidal symptoms (EPS, pyramidal tract- collection of neurons from the cerebral cortex to the spinal cord associated with motor functioning). o Voluntary movement deficiency o Parkonsonian-like motor slowing o Involuntary movements (tardive dyskinesia) Anti-Ach effects: suppressed secretion of saliva/sweat. Hypotension -Atypical antipsychotics- no motor EPS but increased likelihood of diabetes (causes weight gain).

Dopamine hypothesis of schizophrenia: -support: -refute: All antipsychotics are in some way DA receptor antagonists. Psychostimulants (cocaine, amphetamine) increase dopaminergic transmission and induce a psychotic state. Schizophrenic patients dont have excess DA in their brain tissue No elevated DA release rates (measure DA metabolites) No upregulated dopamine receptors

Weinberger DA hypothesis:

-VTAPFC, VTAAcc (limbic sites), PFCVTA (inhibitory), PFCAcc (inhibitory) -Negative symptoms of schizophrenia caused by an underdeveloped mesocortical (VTAPFC) system. -Underdeveloped mesocortical system causes decreased inhibitory effects of the PFC causing an overactive limbic system and the positive symptoms of schizophrenia. -schizophrenia work has focused on frontal lobes as reduced prefrontal activation has been seen in schizophrenics. -similarities noted between behavioral effects of NMDA receptor antagonists (ex. PCP) and schizophrenia. -Moghaddam and Adams:

Found that PCP enhances glutamate release in the accumbens. Same effect is not observed when rats are treated with LY354740 (mGluR agonist) mGluR (metabotropic glutamate receptor) is on the presynaptic terminal. Binding of an agonist causes metabolic breakdown of glutamate, decreasing glutamate transmission. MGluR feedback loop is protective since excess glutamate can be toxic. Since mGluR is known to decrease glutamate levels and schizophrenia is associated with excess glutamate, mGluR agonists are potential schizophrenia treatments.

-PCP and ketamine are used to induce an animal model of schizophrenia. -NMDA receptor KO mice exhibit asocial behavior (potentially mimicking schizophrenia symptoms). Behavior is reversed with mGluR agonist. -Interaction between dopamine and glutamate in schizophrenia: Increased DA causes a neuron to be more responsive to glutamate. Brain arousal systems: -EEG-electroencephelogram -brain waves measured in cycles per second (Hertz). -deeper sleep yields slower waves and increasing synchrony (simultaneous firing of neurons causing higher amplitude of brain waves-Delta activity). -Moruzzi and Magoun MRF awareness pathway: Electrical stimulation of the midbrain reticular formation (MRF) causes fast, desynchronous brain activity. Follow up work by others showed that a lesion in the MRF causes a coma like state. -Reticular activating system (RAS) awareness system: Determines level of alertness/sleep wake cycles. Shut down during sleep Stimulation of RAS causes EEG desynchrony. -Pathways of MRF: Dorsal- through the thalamus. MRFmedial thalamus (NT: Ach) medial thalamusglutamate release to other brain areas.

Ventral- through the basal forebrain. MRFbasal nucleus of Mayner (NT:Ach). BNMreleases glutamate. Ventral pathway is more critical for causing EEG desynchrony.

-ACh and acetylcholinesterases: ACh is indirectly responsible for glutamate release in awareness systems. Acetylcholinesterase (AChE)-breaks ACh down into choline and acetic acid. AntiAChE (anticholinesterase)-binds to AChE and prevents breakdown of ACh (potential treatment for Alzheimers because Alzheimers is associated with degeneration of the basal nucleus). -Otto Loewi: Connected two frog hearts in solution with a tube. Electrical stimulation of the vagus of one heart slowed it down. After a delay, heart two slowed as well with no direct electrical stimulation. Discovery of chemical neurotransmission (ACh responsible in this case for slowing of the heart rate). -Nerve gases contain anticholinesterase to slow the heart (inhibits the breakdown of ACh). Antidote: atropine (ACh muscarinic receptor antagonist). -Atropine contained in the Belladonna plant can be used to dilate pupils. -Scopolamine- another muscarinic anticholinesterase found in Deadly Nightshade, Jimsen Weed, Mandrake and Henbane plants. -Effects of anticholinesterases: Mental confusion Sensory distortions (seeing something everyone sees but interpreting it differently) Hallucinations (primarily visual) Amnesia -lateral geniculate nucleus (LGN)- primary relay center for visual information received from the retina of the eye. Found inside the thalamus of the brain. -anticholinergic drugs induce sleep like synchrony by decreasing ACh signaling in the awareness pathway. -structures of the brain arousal/awareness system: Locus coeruleus (LC)- norepinepherine Raphe- serotonin Tuberomammillary nucleus (TMN)- histamine

 -LSD:

Lateral hypothalamus (LH)-hypocretin

-lysergic acid diethylamid. Synthesized in 1938 by Albert Hoffman. -Looking for a drug to treat migraine headaches. -Investigated by the U.S. government as a potential method for North Koreans brainwashing U.S. soldiers. -psychomimetic-mimics psychosis -psychedelic-expands consciousness/awareness. -Timothy Leary- professor at Harvard who advocated the use of hallucinogens. Was fired for experiments with human subjects involving LSD. Mechanism of LSD: Early thinking: -LSDs structure is like that of serotonin. -LSD blocks serotonin receptors (but 2-bromo-LSD does too, and it isnt hallucinogenic). -LSD increases [5-HT] and decreases [5-HIAA] (metabolite of serotonin). -LSD decreases raphe firing; found mediated at 5-HT1A autoreceptor (autoreceptoron the cell body and responds to the neurons own transmitter. Inhibitory effect). -Theory was that the raphe served as a filter for external stimuli, allowing for selective attention. LSD shuts off raphe and awareness is unfiltered. -LSD turns off the firing of locus coeruleus cells as well. Raphe and LC are turned off during REM sleep. Problems with early thinking: -Buspirone (anxiolytic) decreases raphe firing but isnt hallucinogenic. -Raphe firing returns before behavioral recovery in cats. -Behavioral tolerance w/o tolerance to effect on raphe firing. -Raphe destruction enhanced the 5-HT syndrome of LSD. The current thinking: -5-HT2A antagonists block the 5-HT syndrome from LSD. -Chronic treatment with MAOIs downregulates 5-HT2A receptors and blocks effect of LSD in humans. -Hallucinogenic potency of numerous drugs correlates 0.94 with affinity for 5-HT2A receptors. This is true of both indole- and catechol-type hallucinogens. So, hallucinogens seem to act via activation of 5-HT2A receptors. Other hallucinogens and commonalities with LSD:

-Mescaline hallucinogen derived from the Peyote cactus. -Psilocybin- psychoactive ingredient in magic mushrooms. -Experiental typewriter- different keys represent different visual experiences. Developed to record the experiences of LSD. Problem: LSD inhibits motor control. Jacksons theory of hallucinations: -Many conditions, not just drugs, evoke hallucinations: sleep deprivations, solitude, anoxiac(low oxygen), crystal-gazing -Memories are normally suppressed by processing sensory inputs during normal consciousness. -The conditions which evoke hallucinations impair normal sensory processing, allowing memories to pop out into awareness. These are hallucinations.

Questions: What is the relationship between NMDA receptors and glutamate? How does PCP blocking NMDA receptors increase glutamate transmission? How do NMDA receptor antagonists mimic schizophrenia? Clarify the relationship between PCP, NMDA receptors and mGluR. How is an increase in ACh a potential Alzheimers treatment? If the basal nucleus degenerates in Alzheimers, what good is increasing ACh? What is serotonin syndrome?