the addicted brain

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THE ADDICTED BRAIN _ COURSERA JOANNA JU INTRODUCTION - 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 - 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

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Page 1: The Addicted Brain

THE ADDICTED BRAIN _ COURSERA JOANNA JU

INTRODUCTION - 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, 5th 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- 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

- 1) ALCOHOL

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- 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|82.5o Tobacco Products|68.8o Marijuana and Hashish|42.0o Cocaine and Crack|18.3o Hallucinogens|14.8o Prescription Painkillers|13.8 (opiate)o Inhalants|8.6o Sedatives|3.0o Heroin|1.6 (opiate)

- ECONOMIC COST Estimated cost to society due to illegal drugs = $181 billion/yrAlcohol: $185 billion/yrTobacco $193 billion/yrTotal $559 B/yrIn 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 - 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, don’t 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- 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 longerThus, tests = search for metabolites of certain drugs DRUGS AND THEIR METABOLITES = PRESENT IN URINE AND BLOOD

DETECTING DRUGS IN THE BODY- 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, individual’s compromising metabolism

- Screen = focus on detecting metabolite because metabolite may have longer half-life presence - Drug|detection time

Cocaine(metabolite)|2-5daysCannabis(metabolite;chronic user)|30-60daysMorphine|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

- 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

- Post-synaptic thickening = important for synaptic transmission - Dopamine neurotransmitter

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- 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 - 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- 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 acetate and choline (inactive substances)

- Neurotransmitter can have multiple receptors

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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 - 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

- NIAAA = no more than 14 drinks per week for men and no more than 7 drinks per week for women otherwise… dependence = addiction can occur

- Effects of ethanol: loss of muscular coordination, changes in mood, personality, behavior, mental impairment, obvious intoxication, coma

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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 - 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 o Causes 5M premature deaths worldwide/yro Reduces lifespan 10 yrso 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 acetylcholineo Bind to receptor and opens channel = ion receptor channel

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- 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 Dopamine have pre-synaptic = nicotine taken = dopamine levels increase in nucleus accumbens and prefrontal cortex

o Alpha4-beta2 subtype may be responsible for this effect

o Affects other neurotransmitters = serotonin, glutamate, opioid peptides- 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 - Plants = cannabis sativa, cannabis indica = contain mind altering compounds =

cannabinoids = THC and CBD (cannabidiol) - 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

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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 don’t 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 - 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

- 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:

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- 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 blockero 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) 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 - Drugs that alter consciousness by inducing sensory and perceptual distortions (or something

that isn’t 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 = stuporous, immobile state)

o Effects can lead to injuries from accidents, fights, falls o Addicting o Intoxication = disorientation, hallucination, delusion, and coma at high doses

- PCP interferes with major excitatory neurotransmitter = inhibits 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 - 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

- Effects = reduce pain, euphoria, tolerance +addiction, relaxation, constipation, slow breathing (death from overdose), constrict pupils, nausea and vomiting

- OPIATE OVERDOSE - Addicts take drugs = satisfy craving or avoid withdrawal feel euphoric, deal with physical or

psychiatric conditions

- Treatment medications = methadone (opiate itself but reduce drug craving),

naltrexone (opiate blocker), buprenorphine, suboxone, clonidine

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- Opiates stimulate receptors for endogenous opioid neurotransmitters - 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)

o 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

SEDATIVES, ANTI-ANXIETY AGENTS, & HYPNOTICS - 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)

o NonBz – zolpidemo 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)

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- GABA binding site = distinct from BZ binding site - By itself BZ binding to receptor has no effect, only effect when GABA present

o NT modulators - BZ can cause withdrawal symptoms (anxiety, tremor, nightmares, insomnia, anorexia, nausea,

vomiting, seizures, delirium), abrupt withdrawal can be fatal, return of anxiety symptomso 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 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

o ADDICTION = seeking and taking drugs such that there are negative consequences in life Abuse and addiction = continuum of severity of SUDs

INHALANTS - 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

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- 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 condition = sudden sniffing death (due to cardiac arrhythmias and stress)

- Brain damage = result in shrinking

- Damage to bone, heart, kidneys, lungs, increase risk for other diseases

- Often abused by children and adolescents - 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

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- 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 tachycardiaHeadache, 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)

- Caffeine = antagonist at adenosine (A1 and A2a) GPCR receptors and also increases dopamine

o Blocker of adenosine; Caffeine’s actions are opposite to adenosine o Adenosine = inhibit NT release, reduce excitation and convulsions, depression of

locomotor ability and inhibiting actions of heart

NEW AND OTHER SUBSTANCES - 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,

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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 - 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 stageo 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

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- 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

- 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 = 1o 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 drug’s value to animal

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- 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

- 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

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- 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 Pavlov’s 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 - 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 - 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

- 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 - 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 Injection of specific radiolabeled compoundso Compounds contain positron emitting atoms

o Positron (e+) combines with electrons (e-, its antimatter) o 2 gamma rays result from this combination (annihilation) o 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

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- Do not directly show structure of brain - Radioactivity of brain = suggests slice of brain - No radioactivity vs. PET image distribution of D2 dopamine receptors

- Intensity of color = receptors - Hot cell area = radioactivity

DOPAMINE RECEPTORS IN VULNERABILITY & HEALING - 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

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- (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

- 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

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- 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 timeo Chronic group = allowed to self-administer cocaine for longer period o Glucose utilization measured

Result:o Differences in number of brain regions influenced

o Initial group = increased E consumption in caudate, nucleus accumbens o Chronic = more regions activated, putamen (involved in learning and reinforcement)

- Neuroplasticity = capacity of neural networks to change connections and behavior o Weaken or strengthen signalling in specific neuronal circuitso 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 can’t 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 - 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 controlo Academic competenceo Antidrug infoo Strong neighborhood attachmentso Some genetics o Parents and attitudes in homes (discipline, monitoring, and strong bonds) o Enriched environments

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RISK FACTORS - Cross adoption studies

o 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

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- 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

SELF-MEDICATION & CO-MORBIDITY- 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 worseo 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 ito Consequences = elevation of stress-related chemicals, hormones (cortisol, etc.)o Changes in nervous, endocrine, immune systemso 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/cocaineo Early life stresses = affect behavior and vulnerability later in adulthoodo Temporary separation from mom = changes animals forever

- Early life stress early in life affects later life, adulthood - Youth = important target for prevention efforts = don’t 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 aloneo 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 - Vulnerability factors- Personality traits = habitual patterns of behavior, thought, emotion

o Risk taking, sensation seeking, impulsive behavior

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- 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 - 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 rationalityo 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 problemso Biologic/genetic vulnerability o Slowly progressing and chronico Prone to relapseo 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 diseaseso 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

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- Monitoring (only way to concretely and objectively assess the progress)- Judicial mandate, 12-step programs - 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 policieso Drug abuse = public health issue; not criminal or morality issueo Reduce demand through education, prevention and treatmento Reduce and eradicate drug-related illnesso 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

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o Support basic treatment and researcho 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 statuso Illegal drugso Possession = crime depending on quantity and localeo Distributing drugs = greater crimeo 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 -