The Addicted Brain

THE ADDICTED BRAIN _ COURSERA
JOANNA JU
INTRODUCTION
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Native inborn vulnerability using drugs

Financial cost
Addiction: repeated behavior that results in distress or has a negative
impact
Addict vs. Abuser: addiction more serious problem than abuse
Drug dependence: state of physiologic need = physiological signs occur
when stop taking drugs
o E.g., cocaine (feel depression) or opiate addict (diarrhea)
o DMS-5 = professionals who deal with and diagnose drug use and drug
disorders
Diagnostic and Statistical Manual of Mental Disorders, 5 th Ed.
(American Psychiatric Association) problematic use of drugs = SUDs or
substance-induced disorder (avoid word of addict or dependence =
prejudice)
Substance-use disorder (SUDs)= continued use of drug in spite of
problems (impairment, risks to health, and brain changes)
Substance-induced disorder = refer to things caused by drugs =
intoxication, withdrawal.
Gambling disorder
Behavior = something you do in spite of harmful consequences
Drug abuse = brain disorder
Characterized by changes in the chemistry and anatomy of the brain
(underlie and are the cause of addictive behaviors)
If we could reverse some of these changes = then we can treat and even cure
drug users of their addictions
Way changes occur in brain = mediated by drugs acting as receptors
Different drugs have different molecular sites
THE HISTORICAL EVIDENCE

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Form of communication with sun god = cocaine not only used but its effects
unique and powerful = suggest an association with gods (only priestly class
used cocaine)
New testament = Do not get drunk on wine Ephesians 5:18
Poppy flower seed = milk = latex = opium = morphine
Use of drugs = persisting and continuing (long-standing use) = humans are
somehow vulnerable to using drugs (we are ready to take them even if in a
destructive pattern)
Brain is set up to like drugs = brain is co-conspirator in drug use and abuse =
abuse and addiction = brain disorder
Darwin = monkeys also go through same experiences = hint to
vulnerability = appealing to our biological nature
THE 10 CLASSES OF DRUGS

A Tiger Came Munching In Oranges And Pineapples Hurriedly

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1) ALCOHOL
2) TOBACCO (contain nicotine)
3) CAFFEINE (most widely used psychoactive substance in the world)
4) MARIJUANA (THC, tetrahydrocannabinol = active ingredient)
5) INHALANTS (solvents found in glue or gasoline) = major health problem in
3rd world + children
6) OPIOIDS (importance in medicine pain killers)
7) ANTI-ANXIETY AND SEDATIVE DRUGS (medicine)
8) PSYCHOSTIMULANT (e.g., cocaine, amphetamine, methamphetamine)
9) HALLUCINOGENS (PCP = angel dust, LSD = acid)
10) other
Different molecules but all can be abused/addictive
Side effects = loss of control and increased adverse events = toxic side
effects
Increased toxicity w/ repeated use
Toxic side effects (alcohol = liver disease, marijuana = decrease mental and
physical performance)
DRUG USE: A SERIOUS PROBLEM

People aged >=12 years old
Drug|Lifetime Use (2010 Data_SAMHSA)

o Alcohol|82.5
o Tobacco Products|68.8
o Marijuana and Hashish|42.0
o Cocaine and Crack|18.3
o Hallucinogens|14.8
o Prescription Painkillers|13.8 (opiate)
o Inhalants|8.6
o Sedatives|3.0
o Heroin|1.6 (opiate)
ECONOMIC COST
Estimated cost to society due to illegal drugs = $181 billion/yr
Alcohol: $185 billion/yr
Tobacco $193 billion/yr
Total $559 B/yr
In US _ health cost (loss of productivity, legal costs, other expenses)
Preoccupied with finding and taking drugs
After chronic drug use = prefrontal cortex = enhance activity that we
need to reach goals and inhibit irrelevant activities, emotional regulation
Volume of prefrontal cortex (in brain scans) decreases in alcoholics =
schizophrenics
BEHAVIORAL ADDICTIONS
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Disorders = excessive behavior (gambling, internet use, shopping, eating,

watching t.v.) = addictions = needs scientific studies (characteristics of brain
disorder or addiction)

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E.g., Gambling = persistent behavior causing harmful effects in life (loss of

money, dont meet obligation) = cannot cut back, if trying = experience
stress, lie or try to conceal how much you gamble, significant negative effects
in life, gamble after episodes of stress, or relapses
Continued use in spite of negative consequences and relapses after or during
stress = criteria for all addictions
METHAMPHETAMINE = adverse physical/health effects = e.g., insomnia,
weight lost, appearance change, loose teeth, change in school performance
Dependence = state of chronic drug taking = withdrawal experienced if drug
taking stopped
Substance use disorder (SUDs) = use, abuse, and addiction
DRUG DYANMICS: THE FATE OF DRUGS IN THE BODY

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Drugs blood brain (only way to have effects)

Oral = stomach + intestines blood brain
Injections = intravenous
Inhalants = lungs blood
Different absorption efficiencies (all/some absorbed)
Drugs metabolized/changed = chemical modification = result in cessation of
their action = enhance excretion
Enzymes = modify structures of drugs
Metabolism of ethanol = ethanol dehydrogenase + other enzymes
acetylaldehyde
-
acetate (metabolite of ethanol = inactive

substance)
Many different kinds of metabolites possible
DRUG METABOLISM
Drug elimination = drugs and metabolites removed from body mainly from
urine and feces
Clearance = measure of bodies efficiency in eliminating drug
Elimination half-life measure of rate of removal of a drug; the time to
remove/metabolize 50% of the drug
Normally, for 97% of drugs to be eliminated = takes 5 half-lives
Orally taken = needs to be absorbed = reaches peak = then eliminated
according to half-life
Ethanol = metabolized at a steady rate rather than fraction rate
Excretion via urine = drug-presence
Metabolites in urine persist longer
Thus, tests = search for metabolites of certain drugs
DRUGS AND THEIR METABOLITES = PRESENT IN URINE AND BLOOD
DETECTING DRUGS IN THE BODY

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Drug + metabolites accumulate in urine

Screens and tests = detecting drugs and use
Screens (broad assay = identify many types of drugs) vs. tests (specific
and rigorous)
Antibody detection assays = shape of drug molecule detected by
antibodies (antibodies bind to certain shapes) = SCREEN

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After detecting presence of drug in urine with screen = do detailed assay =

test (using blood) = chemically rigorous and highly specific = tests (e.g., gas
chromatography and mass spectrometer)
Drug screening in urine = excretion varies in different people, detection
window depends on how drug well absorbed, metabolized, individuals
compromising metabolism
Screen = focus on detecting metabolite because metabolite may have longer
half-life presence
Drug|detection time
Cocaine(metabolite)|2-5days
Cannabis(metabolite;chronic user)|30-60days
Morphine|2-4days (only directly, not metabolite)
vary depending on drug and individual
screens usually rely on antibodies to indicate the presence of a drug in the
urine
Less expensive than tests
SYNAPTIC TRANSMISSION: THE TARGET OF ADDICTING

DRUGS
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Drug brain positive experience take again

Synaptic transmission = neurotransmission
(presynaptic) Action potential axon nerve terminal neurotransmitters

released diffuse across synaptic cleft receptors (neurotransmitters bind)
activation of postsynaptic cell another action potential/impulse axon,
etc
Circuits maintains = alternating electrical and chemical signaling to maintain
activity and produce function
Synapse = most important in drug function (e.g, antidepressants,
antipsychotics)
Vesicles line up along membrane = to release their contents

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Post-synaptic thickening
= important for synaptic transmission

Dopamine neurotransmitter
Nerve terminal (vesicles) release into synaptic gap neurotransmitter
receptors of post-synaptic neuron
Signalling action has to be eventually stopped = neurotransmitters must be
removed = signalling must be discrete == neurotransmission is an on and off
process + quick
Dopamine = removed from synaptic space by transport = taken back up into
nerve terminal = REUPTAKE
Neurotransmitters = made in cells, stored in vesicles, released by electrical
impulse, interact w/ receptors, and removed from receptors
Neurotransmission = release of neurotransmitter, receptor interaction,
removal from receptor
- NTs: e.g., dopamine, acetylcholine, GABA, glutamate,

Enkephalins, Serotonin, Endocannabinoids, Adenosine,
Endorphins
-
Psycho-stimulants = cocaine works through dopamine

Nicotine bind to acetylcholine receptors but later involve dopamine
NEUROTRANSMITTERS: THE CHEMICAL MESSENGERS IN

THE BRAIN
-
NTs = potent, active substances, set off signals in the brain, controlled by
evolutionary forces
o Synthesized when needed (e.g., when levels go down)
o Depolarization = released from terminals
o Released into specific space where there are receptors
Uptake (e.g., dopamine) = increase efficiency of neurotransmission = the
neurotransmitter is re-released + also restricts spread of neurotransmitter
Neurotransmission = very rapid (fractions of s)
Disruption in overall process = dysfunction/disease
Drugs work by altering neurotransmission
Receptor = molecular sites where neurotransmitters bind == signal
NT receptors: G protein coupled receptors, ion channels (changes in charge
distribution)
COCAINE & NICOTINE

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Cocaine blocks transporter
= blocks removal of dopamine from

synapse = increase level of dopamine in synaptic space and receptor
stimulation
o Cocaine binds and blocks dopamine transporter
Acetylcholine = drug nicotine = ion channel receptor = neuro
excitation
o Binds to acetylcholine receptor channels open ion flow
Neurotransmitters = very rapid, levels controlled by brain mechanisms

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Drugs = no brain mechanisms, levels determined by user (receptor

stimulation gets out of control) (alter neurotransmission profoundly), long
lasting (determined by half-life in blood)
Acetylcholine removed receptors by being broken down = by enzyme
acetylcholinesterase
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acetate and choline (inactive
substances)
Neurotransmitter can have multiple receptors
o E.g., acetylcholine = ion channel and GPCRs
o Dopamine = 5 subtype GPCRs
Multiple receptors = multiple locations
Cocaine = alert, stronger, energetic, powerful, euphoric (stimulant effects)
Sigmund Freud = third scourge of mankind after alcohol and opium ==
cocaine
DRUGS ARE MULTIFUNCTIONAL

-
Shape of drug molecule complementary to shape of receptor = lock and key
binds to
-
2 different sites
(receptors)
Fit into more than one molecular site = multiple effects = different places =
multi-functionally
Cocaine can reduce bleeding, produce euphoria, cause addiction,
and act as a local anesthetic
Drug receptors widely distributed = different receptors
Drug dynamics = absorption, metabolized, excreted
Urine screens = antibody detections = drug/drug class presence tests (GC
& MS)
NTs tightly controlled + packaged
ALCOHOL
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10 classes of drugs: Alcohol, tobacco/nicotine, caffeine, cannabis, inhalants,

opioids, sedatives, psychostimulants, hallucinogens, other
CH3CH2OH ethanol
Most used and abused drug
Rank 3rd in disease impact (US), 8 million dependent drinkers, associated w/
1/3 cases of liver cirrhosis, leading cause of traumatic injuries
Lowest impact when = weekly intake of no more than 5 men and 2 for
women
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14 drinks per week for men and no more

than 7 drinks per week for women otherwise dependence = addiction
NIAAA = no more than
can occur
Effects of ethanol:
loss of muscular coordination, changes in

mood, personality, behavior, mental impairment, obvious
intoxication, coma
Dependency chart:
Withdrawals = tremor, insomnia, nausea, hallucinations, anxiety, seizures,

death
Mechanism: release dopamine in reward-related areas of brain;
opioid systems involved; opioid blockers reduce drinking;

increases GABA (inhibitory transmitter) activity, blocks
NMDA glutamate receptor
Ethanol broken down by enzyme product acetate (inactive) =
terminated
Metabolism (4-5 h)
Synergistic + sedative
effects
Produces cell death in brain
NICOTINE
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Addicting substance of tobacco

Nicotine = cognatic enhancer = improves attention, memory, computation
and motor abilities, relaxation and activation where blood P, heart rate and
cardiac output increases = comorbidity
Schiz, ADHD, depression = higher level of cigarette smoking
o Produces dependence + chronic smoking
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Causes 5M premature deaths worldwide/yr

Reduces lifespan 10 yrs
Associated with COPD (pulmonary disease), lung cancer,
cardiovascular disease
75% want to stop, 33% try to stop, but 3% actually stop = widespread
relapse
Nicotine receptor = receptor for acetylcholine
o Bind to receptor and opens channel = ion receptor channel
o
o
o
Nicotine receptors = bundles of proteins or subunit proteins =

protein composition of nicotine receptors vary in different parts of brain
Nicotine gets into blood = enters brain quickly = within seconds after puff
Binds to receptors and opens ligand-gated ion channels

(acetylcholine receptors) causing influx of Na+, efflux of K+, and
sometimes influx of Ca2+
Can break down acetylcholine but not nicotine = effects linger over time in
brain
Nicotine receptors can be pre-synaptic
o Receptors on nerve terminal = pre-synaptic (alter
neurotransmitter release to synapse)

o
o
o
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dopamine levels
increase in nucleus accumbens and prefrontal cortex
Alpha4-beta2 subtype may be responsible for this effect
Affects other neurotransmitters = serotonin, glutamate, opioid
peptides
Dopamine have pre-synaptic = nicotine taken =
Withdrawal symptoms = irritability, frustration, anger, anxiety, depression,

reduced concentration = high relapse
Electronic cigarette = vaporize nicotine solution (inhalation) = eliminates
smoke toxicity = craving without smoke (like nicotine patch)
MARIJUANA
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Plants = cannabis
compounds =
sativa, cannabis indica = contain mind altering
cannabinoids
THC and CBD (cannabidiol)
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Cannabionoids = get user high, relaxed, more social, calm, mildly euphoric
state; effects last 2-4 hrs

Medical marijuana = pain, nausea, weight loss in AIDS patients
Can induce transient schizophrenia-like symptoms
Impair memory, judgement, problem-solving and balance
Interact with endogenous substances (naturally-occurring) = the
endocannabionoids (endoCBs) = neurotransmitters that are involved in

many physiological functions
o Can be agonist at endoCB receptors
o E.g., Anandamide and 2-AG
endoCBs = inhibit release of other NTs by retrograde action = act at
post-synaptic side and act back at the pre-synaptic nerve terminal
o EndoCb receptors = CB1 (widely distributed in brain) CB2
(mainly in periphery) = both G-protein coupled receptors
Drugs dont always look like the NTs they react with
endoCBs are broken down by enzymes = FAAH and MAG

lipase (fatty acid amide hydrolase and monoacyl-glycerol lipase)
try to modify naturally occurring substances with external substances

(medications)
endoCB system = new medication synthesized based on this system and its
receptors
cannabinoids are safer than other medications
marijuana causes impairment of many functions leadings to accidents and
erroneous judgement
PSYCHOSTIMULANTS
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cocaine (vasoconstrictor + local anesthetic) and

amphetamine (treats ADHD, narcolepsy) = approved medical uses
smoking + injecting = fastest = to brain
hemorrahages + stroke = potent vasoconstrictors
= reduce size
of BV and raise BP
cocaine from plant = Erythroxylum coca and Erythroxylum novogranatense

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hydrochloride salt form = crack cocaine (different form)

o vaporizes at lower temperature (90C) therefore can be
smoked than cocaine HCl (190C)
o vapors very efficiently transfer cocaine to blood and brain
o more addicting and easier to use
2 types of amphetamine:
Cocaine vs. amphetamines = very similar user experience

o Significant half-life difference (amphetamine = longer)
Psychostimulants affect many NTs (act at transporters)
o Dopamine transporter is the target for reinforcing effects
o Cocaine is a DA reuptake blocker

o Amphetamine are uptake blockers and releasers
Cocaine blocks transporter dopamine builds up in cleft greater receptor

stimulations
Amphetamine blocks transporter + rides transporter into nerve terminal
cause release of more dopamine
o Cocaine = only blocker, amphetamine = blocker +releaser
- Amphetamine = MDMA (molly), MDE = Eve, Ecstasy (MDMA

+ MDE)
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o Stimulants and also hallucinogens = complex effect

Acute effects (cocaine and meth) = euphoria, confidence, grandiosity,
enhanced sexual performance, increased sensory awareness, insomnia
Chronic effects = panic disorder, paranoia, schiz., tolerance (euphoric
effects), addiction, withdrawal, toxicity (neuronal damage)
Toxicities = addiction, long lasting brain changes, elevated BP, withdrawal
(depression and dysphoria = crash), psychosis
HALLUCINOGENS
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Drugs that alter consciousness by inducing sensory and perceptual

distortions (or something that isnt there at all)
E.g., LSD, Ecstasy
- PCP (phencyclidine) = angel dust
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Dissociative anesthetics
= produce feelings of separation of mind and

body
PCP = IV administration cause schiz. Like state ( psychosis and
catatonia
o
o
o
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= stuporous, immobile state)

Effects can lead to injuries from accidents, fights, falls
Addicting
Intoxication = disorientation, hallucination, delusion, and coma at high
doses
interferes with major excitatory neurotransmitter = inhibits
PCP
glutamate neurotransmitter at NMDA type glutamate receptor
LSD = acid = visual hallucinations (sometimes lead to suicide) =
persisting perceptual experience even when drugs are not
present
o Binds to serotonin receptors, stimulates 5HT-2A receptors
MDMA, Ecstasy = both simulant + hallucination
Neurotoxicity of MDMA == degeneration of nerve terminals of
neurons containing NT serotonin = neuronally destructive
Hallucinogens (2 types) = PCP type and others (e.g., LSD)
OPIATE DRUGS
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Medicine = reduce pain

Prescription painkillers and sedatives
Reduce moderate to severe pain effectively
Morphine = natural product = poppy plant = extracted by cutting
surface of seed pod = milk harvested
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Effects = reduce pain, euphoria, tolerance +addiction, relaxation,

constipation, slow breathing (death from overdose),
nausea and vomiting
constrict pupils,
- OPIATE OVERDOSE
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Addicts take drugs = satisfy craving or avoid withdrawal feel euphoric, deal
with physical or psychiatric conditions
Treatment medications = methadone (opiate itself but reduce drug
naltrexone (opiate blocker), buprenorphine, suboxone,

clonidine
Opiates stimulate receptors for endogenous opioid
neurotransmitters
craving),
Opioid NTs = opiates react with = NTs (peptides or chains of aa)
o Endogenous Opioid Peptides (Enkephalins; Met- and

Leu-, Endorphins, Dynorphins, Nociceptins)
- Opioid receptors = all GPCRs = Mu (for analgesia, euphoria,
respiratory depression, physical dependence), Delta (anal,
physical dep.), Kappa (anal. Dysphoria, anticonvulsant
effects, dissociative effects)
These have subtypes (so there are many opioid receptors = with diff.
distributions in brain = variety of effects)
Act through systems already in brain = natural system
o
SEDATIVES, ANTI-ANXIETY AGENTS, & HYPNOTICS

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Sedative (calming agent), hypnotic (agent that facilitates sleep; often higher
dose than sedative), antianxiety (anxiolytic)(similar to sedative; reduces
anxiety)
Drug types:
o Benzodiazepines (BZs) Xanax and Valium (very high doses
alone do not automatically cause death by overdose = thus, relatively
safe = most used medication in this class, but when taken with other
depressants = increase lethality of those substances; e.g., with
alcohol)
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o NonBz zolpidem
o Carbamates meprobamate (not really used anymore)
o Barbiturates secobarbital (not really used anymore)
o NonBzs buspirone (little or no abuse or addiction)
o Alcohol or marijuana
Valium (diazepam), Xanax (alprazolam), Ativan (lorazepam), Klonopin
(clonazepam), Halcion
Effects of BZs = sedation (up to intoxication), decreased anxiety, muscle
relaxation, sleep, amnesia, anticonvulsant activity, and addiction
Acts on GABA-A receptor (increase the action of GABA) = make inhibitory
effect of GABA greater
Gamma aminobutyric acid = major inhibitory NT in brain = both ion channel
receptors and GPCRs
Ion channel receptors (GABA-A) mediate flow of Cl- ions
GABA-A receptors = have multiple subunits + grouped as pentamers (5
proteins bundled together)
E.g., GABA-A (structurally similar to nicotine)
GABA binding site = distinct from BZ binding site

By itself BZ binding to receptor has no effect, only effect when GABA present
BZ can cause withdrawal symptoms (anxiety, tremor, nightmares, insomnia,

anorexia, nausea, vomiting, seizures, delirium), abrupt withdrawal can be
fatal, return of anxiety symptoms
o Should stop gradually not abruptly
NT can excite postsynaptic neurons or inhibit them. If inhibited, they will
require even more excitation to initiate a nerve impulse. GABA is the major
inhibitory NT in the brain
TOBACCO = addicting substances = nicotine, acetaldehyde, norharmane,
anabasine
DEPENDENCE VS. ADDICTION
o DEPENDENCE = state of chronic drug taking where withdrawal is
experienced if the drug taking is stopped. Withdrawal can be serious
state and can drive additional drug taking
o NT modulators
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e.g., taking opiates for chronic pain = life bearable = dependent on

medication and experience some degree of withdrawal if abruptly
stopped taking med. But not necessarily addicted (no seeking and
drug taking having negative consequences)
dependence can be tolerated
ADDICTION = seeking and taking drugs such that there are negative
consequences in life
Abuse and addiction = continuum of severity of SUDs
INHALANTS
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Usually (l) or (g) fumes inhaled (paints, glues, fuel)

Diverse = classified = volatile and (g)
Solvents = glue, paints, paint thinners, motor fuels
o NO = anaesthetic (g) = laughing (g)
o Alkyl nitrites found in room deodorizers
o Propellants and fuels
Acute effects = (first time effects) = excitation (rush) followed by depression,

cognitive impairment, loss of coordination, slurred speech, irritate eyes and
lungs, high concentration product hallucinations, seizures, coma, lethal
sudden sniffing death (due to cardiac arrhythmias

and stress)
condition =
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Brain damage = result in shrinking
Damage to bone, heart, kidneys, lungs, increase risk for other diseases
Often abused by children and adolescents

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Diverse class of drugs

Toluene = paint and paint thinners = generalized depression of brain =
inhibiting excitatory neurotransmitter receptors

- Anesthetics = enhance inhibitory NTs receptors like GABA-A
and glycine
- NO = inhibits excitatory NMDA and other ion channel
receptors
- Common theme = reduction or blockade of excitation and the
enhancement or the increasing of inhibition at synapses in the
-
brain
No proven medications thus, treat symptoms
Inhalants = easily obtained, used but addicting and very toxic
Inhalants are unique group of abused substances because they are classified
according to their route of administration instead of their pharmacologic
profile or mechanism
Common = INHIBITION OF NMDA AND ENHANCMENT OF GABA-A RECEPTORS
CAFFEINE
- Mild stimulant
Psychoactive drugs = alter the way the mind functions

Found in plants
With dependence and reducing use = restlessness, nervousness, insomnia,
frequent urination, GI disturbance, muscle twitching, fast heart rate
tachycardia
Headache, drowsiness, dysphoria, depression, irritability, decreased
concentration
14% used caffeine despite harm and advice to stop or reduce
45% reported unsuccessful efforts to control use (from DSM)
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= antagonist at adenosine (A1 and A2a) GPCR

receptors and also increases dopamine
Caffeine
o
o
Blocker of adenosine; Caffeines actions are opposite to adenosine

Adenosine = inhibit NT release, reduce excitation and convulsions,
depression of locomotor ability and inhibiting actions of heart
NEW AND OTHER SUBSTANCES

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Anabolic steroids
(derivatives of testosterone), natural products

(betel nuts for mild euphoria, kaba from south pacific pepper plant, khat
contains cathinones),
bath salts
(mephedrone found)
Anabolic steroids = promote growth of skeletal muscle = used by athletes +

body builders = increase sexual characteristics = adverse effects (abnormal
breast development, heart attacks, liver cancer), alteration of hormonal
systems (testicular shrinkage), skin problems (acne, oily skin)
Withdrawal symptoms = mood swing, restlessness, depression, cravings (up
to yr)
Bath salts = emerging group related to stimulants, amphetamine, cathinone,
and MDMA
o Mephedrone, pyrovalerone producing stimulant and perhaps
hallucinogenic effects
o Produce intense cravings + addictive
ANIMAL MODELS
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Before study:
o experimental plan must be described in detail and approved by
committee
o Required to be beneficial and nontrivial; discomfort must be
minimized
o Experimental plan must include vet care at every stage
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o Lab inspected to ensure appropriate animal care

Good animal models:
o Produce results that are similar to those previously found in humans
(a validation)
o Predict results that will be found in humans (including treatments)
o Used to elucidate underlying brain mechanisms that cause results
Animal models: Drug self-administration and conditioned place
preference
Passive drug administration
(injected)
Drug self-administration (animal chooses to take drug via lever)
Learns which is the drug lever and saline is ignored

Dose and frequency of dosing controlled by computer, thus no overdose
Animal has positive sensation + association with lever
Increasing dose per injection results decrease in rate of lever pressing

Lower doses, as dose increases, press lever more (drug = positive) but at
higher dose (dose so high) sated by previous injection thus press lever less
often
Drug abuse = physiology shared with animals (not a human problem)
Naltrexone and Baclofen = treating alcoholism
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Number of lever presses = y-axis, and time slots = x-axis

Animal has 11 drug-self administration sessions
o 1: which lever delivers cocaine (acquisition phase given lever is
associated with positive feelings)
o Maintenance phase (no change in amount of lever presses)
o Session 12 (drug with-held) = extinction phase (little lever phases
= no drug award)
o Session 26: (E14) Animal stressed, given injection of cocaine by
invigilator
o Reinstatement (go to lever and press)
Break-point = measure how much work animal will do to get drug
Animal quickly learns changes in lever and switches in preference to get drug
Ratio number of lever presses per injection
o Injection is given every time there is a lever press; ratio = 1
o Fiver lever presses ; ratio = 5
o As ratio increases, point is reached where animal gives up = break
point = lose interest (work and time required)
Measure of drugs value to animal
Experiment: CART Peptide (brain chemical)
o CART peptide = reduce action of cocaine when injected into brain
o Drug employed in break-point = lowered break-point, suggesting
that CART lowered value of drug to animal
o Substance similar to CART might be good medication for cocaine
Animal model: Conditioned Place Preference (CPP)
Fewer health risks (no surgery required)
Injection + chambered box (dissimilar chambers on each end)
Less complicated than drug self-administration
Photocells in boxes = measure how much time animal spends in each
chamber
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Training phase
(injected with drug or saline) followed by testing phase

Drug = grid floor, saline = smooth (associate feeling of drug with specific
chamber)
If drug = rewarding and positive, on test day (no drug given), animal spend
time in chamber where it associates with drug (animal trying to find
rewarding experience)
- Associating environment with drug

- Aversive drug (unpleasant or painful) = animal will avoid that chamber
- Test useful for both preferred and aversive drugs
Animal model: Electrical Self-administration

o Animals press levers to self-stimulate electrically rewarding centres of
the brain
Presence of rewarding drugs reduces amount of electrical stimulation needed
to satisfy animal; since some pleasure already present from drug, less
electrical stimulation needed
Drugs interact w/ naturally occurring brain centres that provide positive
feelings
Cue = reminder or drugs or taking drugs = certain places, items, people =
causes relapse
o Stimulation = recognition
o Just the sight can turn on cravings
o E.g., similar to Pavlovs dog (salivating at sounds of dinner bell even if
food not present)
Desensitization = process where we confront our cues until they no
longer create drug urges
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Single drug with many effects = same drug receptor exists in many different
functional circuits/regions that promote different physiological action
o Drug interact w/ many different kinds of receptors for diff. NTs (also in
diff. fnal areas of brain/body)
E.g., NT acetylcholine, nicotine = psychic stimulant, BP elevator, gut muscle
contractor
o Nicotine/acetylcholine receptors found in all of these areas
Drug can interact w/ diff. receptors = involved w/ diff. NTs
o E.g., ethanol = interacts = GABA or glutamate receptors
DOPAMINE, REWARD, AND SURVIVAL

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Reward circuits are critical to human survival (feel good when we do

something for survival = eating, drinking, sexual activities)
Reward system for survival
Drugs activate these systems accidently
Circles = brain region

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Cocaine blocks removal of dopamine in synapse = increase stimulation =

inhibit dopamine transporter (dopamine-cocaine and dopamine-reward
connection)
Small probe placed in rat brain = measure dopamine levels in that area =
extracellular or synaptic levels
Before cocaine given = synaptic dopamine level stable; cocaine given =
dramatically increases level of dopamine; as cocaine levels fall = transporters
regain ability to function and dopamine levels fall back to normal (in nucleus
accumbens)

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Extracellular levels connected to receptors

Psychostimulants, opiates, ethanol, cannabinoids, nicotine, caffeine = all
increase dopamine
Dopamine = important regulator and modulator of drug reward
DOPAMINE & NATURAL REWARDS

-
Sexual activity and dopamine levels
Dopamine is important modulator of reward, but not the only factor = there
are many diff. NTs and other reward systems
Dopamine is involved in attracting various stimuli
BRAIN IMAGING & PET SCANNING

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Post-mortem autopsy
PET = positron emission tomography = measure metabolism in various brain
regions, levels of diff. proteins, receptors
MRI = magnetic resonance imaging = measure structure, volume and
structure of brain
FMR = functional magnetic resonance = measure relative activity of various
brain regions
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- Annihilation
o
o
o
o
o
Injection of specific radiolabeled compounds

Compounds contain positron emitting atoms
Positron (e+) combines with electrons (e-, its antimatter)
2 gamma rays result from this combination (annihilation)
Gamma rays shoot off in opposite directions
Injection of positron-emitting compound, exact compound given depends on

kind of brain protein that is being measured
Gamma rays detected by circular array of detectors analyzed by computer
and image reconstructed and displayed
PET data = slices through brain = tomography
Do not directly show structure of brain

Radioactivity of brain = suggests slice of brain
No radioactivity vs. PET image distribution of D2 dopamine receptors
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Intensity of color = receptors

Hot cell area = radioactivity
DOPAMINE RECEPTORS IN VULNERABILITY & HEALING

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PET can measure D2 receptor, or measure energy or glucose metabolism

Active regions = greater metabolism
Levels of receptors reflected in brightness of regions

Basal ganglia
(1 month and 4 month = cocaine users)
Drug use reduces D2 levels, return to normal very slow = long time to
heal
Changes in the level of receptors = have functional effects
PET scan of glucose utilization
Normal vs. cocaine absence
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Low levels of D2 receptors are associated with higher vulnerability to

addiction
Levels of D2 receptors are low

D2 receptors of obese, gambling subjects also show reduction
Lower levels of dopamine receptors = greater urge of impulsivity
NEUROPLASTICITY & HOW DRUGS CHANGE THE BRAIN

-
Chronic drug use

Brain imaging = glucose utilization = brain regions most active = more
glucose utilization
Experiment:
o Initial group = allowed to self-administer cocaine for short period of
time
o Chronic group = allowed to self-administer cocaine for longer period
o Glucose utilization measured
Result:
o Differences in number of brain regions influenced
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Initial group = increased E consumption in
caudate, nucleus
accumbens
o
Chronic = more regions activated,

and reinforcement)
putamen
(involved in learning
Neuroplasticity = capacity of neural networks to change connections and

behavior
o Weaken or strengthen signalling in specific neuronal circuits
o Changes in synapses, formation of new synapses, or chemical changes
in neuron
Altering # of NTs released, changing number of receptors, changing signaling

molecules
Changes in gene expression
Altering or activating transcription factors or epigenetic mechanisms
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HOW DRUGS ALTER GENE EXPRESSION: SIGNALING AND

EPIGENETICS
Regulating gene expression = regulating protein levels = NT signal reduction

Signalling = NT = signal that is converted by acting through a receptor, to a
series of biochemical changes within the next neuron
GPCRs = receptor proteins specific for given NT/drug
Inside neuron = trimeric G-protein (composed of alpha, beta and gamma
subunits)
GDP exchanged for GTP

G-protein subunits move away from receptor
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GTP alpha activate enzyme (kinase = which adds phosphate groups), beta
gamma portions affects other enzymes
Subunits finish activations, then GTP converted to GDP, configuration returns
to how it started = complex ready to go again
Many diff. G-proteins + processes = Richness in variety of G-protein
signalling
TF regulators of gene expression
Activation of GPCR via NT or drugs
TF = protein (e.g., jun, fos, CREB) = required to bind to regulatory region
of DNA; helps translate genetic message in DNA to RNA or proteins
Activate TF via phosphorylation
TF bind to regulatory region so DNA = increase RNA and protein

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Signal transduction by NT = normal functioning of brain = drugs inserted into

these pathways dominate NT and change NT function
Drugs alter protein makeup in brain
- Epigenetics = methylate genes in DNA preventing

transcription
o Acetylate histones = DNA cant be expressed or copied
Dopamine = mediator of reward for naturally rewarding activity

o Attracting attention to variety of stimuli
Change gene expression = activate or deactivate TF
Drugs alter NT = altered intracellular signalling = altered activation of TF =
changes in proteins produced by cell
o drugs change chemistry and function of brain
Brain heals slowly = thus, addicts relapse
o Rate of recovery of receptors in the brain after drug use
VULNERABILITY
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Risk or vulnerability factors = tendencies

o Biology (heritability = not fully determining) = genetics 50% influence
o Personality, overall health
o Co-morbidity (coexisting health problems)
o Risk taking, impulsiveness (personality trait)
o Environment (major role) = availability, peer pressure (adolescence),
stress, social stratus, drug awareness (advertising legal drugs)
Genetic predisposition, personality traits and temperament, age at first
exposure, additional co-existing disorders, self-medication, impairment
Protective factors
o Self control
o Academic competence
o Antidrug info
o Strong neighborhood attachments
o Some genetics
o Parents and attitudes in homes (discipline, monitoring, and strong
bonds)
o Enriched environments
RISK FACTORS
- Cross adoption studies
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Sons of alcoholics adopted at birth to non-alcoholic families have a 4

fold greater probability of becoming alcoholic
o Sons of non-alcoholic parents adopted and raised by alcoholic families
did not tend to become alcoholics
genes = DNA = chromosomes
o mutation = change in DNA sequence (single nucleotide, supplication,
insertion, deletion or copy/repair error)
o mutation in gene = likely affect the protein made
loss of function = gene product has no function
gain of function = new product has new or increased function
dominant negative = gene product antagonizes original gene
and its product
lethal = leads to death
back = mutation back to original gene
polymorphism = simultaneous existence of diff. mutations in population
SNPs
SNP in mu opiate protein
found more frequently in group of heroin

addicts
SNP in dopamine receptor alcoholics
Associations of SNPs with addictions
Nicotine receptors = composed of subunits (each made of diff. genes) =
receptors for NT acetylcholine
Bundles of 5 subunits in circle, open core (channel for ions)
o Different kinds of subunits (e.g., alpha 1, beta 2)
o Occurrence of certain SNP in alpha 5 = associated with pleasure from
cigarette and increase in dependence
Composition of receptor for nicotine + dependence
No single mutation or polymorphism causes addiction
Dozens of genes involved in addiction (many genes interact w/ environment)
Without simple genetic determinism = behaviors, environment and
medications can be altered to reduce vulnerability
Mutation in enzyme that metabolizes alcohol causes illness is those drinking
alcohol and mutation reduces drinking = Asian populations
SNP in gene that metabolizes nicotine = more frequent in non-smokers
40-60% variance in inheritability can be traced in genetics
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SELF-MEDICATION & CO-MORBIDITY

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Self-medication = use of drugs by an addict to ameliorate problems other

than addiction
o Everyday problems = stress, grief and loss, crises, violence, trauma,
pain
Addicts frequently have additional coexisting problems = predisposing them
to addiction
o E.g., high anxiety (consume alcohol = to calm)
co-morbid disorders: attention disorders, aggressive behaviors, conduct
disorders, mood disorders, anxiety disorders
o 2 or more disorders exist in same person (same time or one after
another)
o Interact and make worse
o 35% drug users meet criteria for mood disorders
o 45% for anxiety, 50% for conduct/personality disorder
o 29.9% anxiety, 40.9% mood, 33.2% depression, 10.7% social phobia
To stop using drugs = the co-morbid disorders must be treated as well
THE INTERACTION OF VULNERABILITY & RISK FACTORS

-
Stress = set of reactions to event that upsets ideal physiologic equilibrium in

body
o Overall response of body to a demand placed on it
o Consequences = elevation of stress-related chemicals, hormones
(cortisol, etc.)
o Changes in nervous, endocrine, immune systems
o Chronic stress alters immune responses, development: provokes
anxiety, depression, drug use
Stress increases opiate drug self-administration, increases reward value of
drugs, provokes relapses
Children and adolescents most vulnerable to drugs
Younger = use drugs, greater vulnerability later in life
Adolescent rats seek more reward than adult rates (intake of sweetened
condensed milk = greater desirability in puberty than adulthood)
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Adolescence = early development = vulnerability period

Temporary period, immediately after birth, rat mothers typically leave nest to
forage for food, but extended absence = pups stressed
o Experiment = 15 mins separation vs. 180 minute separation (very
stressful) = only during first 2 weeks of life
o Adults = separated from mom 180 mins = greater preference for
alcohol/cocaine
o Early life stresses = affect behavior and vulnerability later in adulthood
o Temporary separation from mom = changes animals forever
Early life stress early in life affects later life, adulthood
Youth = important target for prevention efforts = dont get them even started
with drugs
ENVIRONMENTAL RISK FACTORS

-
Stress, societal status, availability of drugs, peer pressures, advertising for

legal drugs
Experiment (social status + vulnerability)
o Live alone vs. same animals put together in groups of 4
o Group = establish hierarchy (dominant and subordinates)
o Dominant = more aggressive and submitted and groomed
o Experiment measures = determine levels of D2 receptors via PET scan
= vulnerability to take drugs and drug self-administration (how much
drug these animals will take)
o Living together = animals emerged as dominant = increases D2
receptor levels by 20-25% vs. living alone
o Subordinates = no significant changes
o Inverse relationship b/w D2 receptors and vulnerability, this suggests
that dominant animals developed less vulnerability to drug use
o Drug self-administration = dominant = higher D2 = took less cocaine
Social situation changes vulnerability
Dominancy = reduction in stress? Ability to be dominant?
PERSONALITY & JUDGMENT RISK FACTORS

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Vulnerability factors
Personality traits = habitual patterns of behavior, thought, emotion
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o Risk taking, sensation seeking, impulsive behavior

Judgment = way we infuse values into our decisions
o Drugs directly affect judgment (e.g., marijuana = sedating and impairs
cognitive function; hallucinogens distort reality)
o Prefrontal cortex = responsible for self-control and anticipating
negative consequences = make good judgment
Drugs altering pre-frontal cortex

-
Chronic drug use = loss of activity in pre-frontal cortex

o e.g., alcoholics comparable to schizophrenics
reduction in prefrontal cortex = loss of emotional regulation, degradation of

judgment and inhibitions
PROTECTIVE FACTORS/PREVENTION
-
Biological (mutation in alcohol metabolizing enzyme = Asian = Illness from

drinking alcohol; SNP in nicotine metabolizing enzyme gene = found more
frequently in non-smokers than smokers) personal, environmental (parental
involvement, monitoring and positive rewarding env.), exercise, academic
competence, anti-drug education, strong neighborhood, opportunity for
wholesome rewards
actively compensating for bad risk factors = e.g., addiction in family/mental
illness = must work to reverse or compensate for them
Need prevention (understanding risk factors) before giving treatment (too
late) = include protective factors in life
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TREATMENT
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Treatment can reduce drug abuse by half, criminality up to 80%, arrests 64%,
costs of drug-related crime
Treatment = set of activity (e.g., med or changing behaviors) with goal of
reducing or eliminating drugs
Stigma = attitude of disgust associated with being an addict
o Cruel problem, due to lack of info and rationality
o Prevents treatment (we want to avoid problem and topic)
o Prevents addict from coming forward to get treatment (in denial)
Cardiovascular, asthma, diabetes
Atherosclerosis and addicts
o Serious health problems
o Biologic/genetic vulnerability
o Slowly progressing and chronic
o Prone to relapse
o Require change in lifestyle
Addiction is brain disorder like many other diseases found in other organs
o Compares in many ways to atherosclerosis and other chronic relapsing
diseases
o No reason for stigma; must be overcome
Individual therapies evolve and vary
Treatment principles:
o Remain in treatment for duration (3 months = to get control of drug
taking and get the most out) = repetition
o Counseling
o Medications
o Comorbid conditions
Withdrawal = detoxification (good start in treatment)
Brain chain for long time and healing process slow
Avoid relapse = must undergo long-term treatment
Voluntary or mandated treatment (need to want) = urban myth? Does not
need to be voluntary
Monitoring (only way to concretely and objectively assess the progress)
Judicial mandate, 12-step programs

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Medications:
o Opioids = methadone, buprenorphine, naltrexone medications
o Tobacco = nicotine patch, spray, gum, lozenges, bupropion and
varenicline
o Alcohol = naltrexone, acamprosate and disulfiram
Vaccines against drugs
o Injection to produce antibodies = long lasting effects (months) vs. med
dose lasts several hours
o Antibodies do not need to get into brain, enter blood, thus do not have
side effects
o Vaccine stimulates immune system to create antibodies (antibodies
bind drugs in blood and prevent them from getting into brain)
Treatment yields for every dollar $4-7 = saves and reduces overall costs
GOVERNMENT DRUG POLICY

-
Policy: set of guidelines or attitudes about drug abuse and addiction

impacting public health, treatment, prevention and law
o Reflects our vision of present and future (e.g., punishment vs. reducing
harm)
Harm reduction = set of strategies for reducing negative consequences due
to drug use. Includes respect for people who get in trouble with drugs
o Accepts drug as complex disorder and supports providing non-coercive
and non-judgmental help
o Prevent = Drunk driving, poor health, stigma, HIV and STDs, violence,
poor job performance, poor parenting
Clean needle programs
Screen addicts and drug users for disease = free screening treatment
General policies
o Drug abuse = public health issue; not criminal or morality issue
o Reduce demand through education, prevention and treatment
o Reduce and eradicate drug-related illness
o Enact laws supporting drug use reduction = no smoking in public
places
o Avoid harsh laws for possession of small amounts of drugs for personal
use
Support basic treatment and research

Each drug different = individual laws (tobacco, alcohol = legal = more
available, inhalants are toxic, often used by children = glue and fuels,
marijuana toxicity)
o Control availability and educate public
o Some drugs have no medical uses
US drug use has increased despite war on drugs
3% of American adults are in prison, on probation or on parole
Adverse consequences of drug use burden everyone
Fetal alcohol syndrome (FAS)
Need balance: most harm reduction with least degree of regulation/restriction
Control of drugs:
o Availability affect by legal status
o Illegal drugs
o Possession = crime depending on quantity and locale
o Distributing drugs = greater crime
o Legal drugs (tobacco = nicotine, alcohol)
o Age restrictions
o Taxes
Decriminalization = reduce penalties in some cases = possession of small
quantities
o Not legalization
Punishment drives abusers underground
Drug court = appreciates value of treatment as much as crime, punishment
and incarceration
People held accountable for treatment and other obligations (e.g., family)
Court-mandated treatment works
o Adult courts and family courts (family problems)
US, 75% drug court graduates remain arrest free for at least 2 years
Drug courts reduce crime by as much as 45% vs. other sentencing option
$1 drug court investment yields as much as $3.36 in criminal justice costs
Other benefits = savings up to $27 for every $1 invested
Savings from $3000-$13000 per client in reduced prison costs
Drug courts = 6X more likely to keep offenders in treatment
Family reunification rates are 50% higher
Treat drug abuse as a public health problem
Prevention = most inexpensive way
Synaptic transmission = neurotransmission
NTs made in vesicles released by electrical impulse interact with
receptors removed from receptors
NT dopamine act at GPCR
Drugs are multifunction = variety of physiological effects at single receptor,
act at many diff. receptors
o
o
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The Addicted Brain

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The Addicted Brain

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THE ADDICTED BRAIN _ COURSERA

Native inborn vulnerability using drugs

THE HISTORICAL EVIDENCE

THE 10 CLASSES OF DRUGS