Drug Abuse: Outline

1. Drug Abuse: Outline • Why do people do drugs? • Reward System • Common features of drug addiction • Tolerance, withdrawal, craving & relapse • Therapy for drug abuse • Abused Drugs • Opiates, Cocaine & Amphetamine, Alcohol, Benzodiazepines, Nicotine, Cannabis

2. Models of Addiction:Why do people use drugs? • Because they are sinners! (Moral model) • Drug addicts lack will power (moral fiber) • Predominant until middle of 19th century • Treatment: Punishment; Spiritual reawakening • Because ‘they have a problem’ (Disease Model) • There is a biological component to addiction • A constitutional factor: once and alcoholic, always an alcoholic • Predominant in late 19th century, in ‘60s, and in AA • Treatment: decriminalize; total abstinence • Weakness of the model: Addiction is not a ‘single’ disease

3. Models of Addiction: Why do people use drugs? • Because it feels bad not to. Dependence Model • Drugs triggers pleasure • after a while tolerance develops • absence of drug leads to withdrawal • People take drug to prevent withdrawal symptoms • Weaknesses of this model: • withdrawal & dependence are often uncorrelated (e.g, cocaine) • "No doc, craving is when you want it—want it so bad you can almost taste it ...but you ain’t sick ...sick is, well sick" (Childress et al.1988).

4. Models of Addiction: Why do people use drugs? • Because its use is rewarded Reinforcement Model • Drug addiction is a learned pattern of behavior (maladaptive) • Addictive drugs have reinforcing effects • the reward system is activated by • Natural reinforcers (sex, food) and • artificial reinforcers (drugs of abuse)

5. TheReward System: Dopamine Dopamine Activities of survival (sex, feed) activate the reward system Drugs of abuse similarly activate the reward system Electrical stimulation of the reward system is also addictive

6. Electrical intracranial self-stimulation Olds & Milner (1954) stimulation n. accumbens The mind is its own place, and in itself, can make heaven of Hell, and a hell of Heaven. (Satan, in John Milton’s Paradise Lost, book 1, ll. 254–5) Quoted by R. Cardinal VTA dopamine

7. ‘drug addiction is a learned pattern of behavior’ Brief detour on ‘Learning’: operant conditioning • Operant conditioning (aka instrumental learning) • Reinforcing stimulus (dopamine release) follows a particular behavior (lever press, injecting heroin) and thus makes the behavior become more frequent • Skinner’s box

8. Cue-induced Craving: Images of drugs (CS) become associated with the effect of the drug. Dopamine activation (UR) shifts from US (drug) to CS (context, friends, drug stimuli) • Drugs with fast absorption are most addictive (close temporal link between behavior and drug effect) Pavlov’s dog: US  UR (meat -> salivate) CS + US (bell + meat) CS  UR (bell -> salivate) CS & US are in close temporal proximity ‘drug addiction is a learned pattern of behavior’ Brief detour on ‘Learning’: Classical conditioning

9. Animals work for reinforcement for several reasons, including... operant conditioning Classical conditioning

10. during ingestion of a preferred food • to a cue associated with food (CS) during Intracranial self stimulation • during IV cocaine self-administration • to a cue associated with cocaine (CS) • during sexual behavior • in anticipation of sex Dopamine release in the nucleus accumbens

11. Common features of drug addiction Tolerance: • the need of larger doses to obtain the same effect Withdrawal: • Usually starts hours after stopping drug use • Different drugs produce different withdrawal symptoms from the very mild (cocaine) to the very severe (alcohol)

12. Craving & Relapse: • During abstinence, prefrontal cortex and the anterior cingulate cortex (ACC) of cocaine abusers is hypoactive • Context previously associated with cocaine leads to increased activation of ACC • In rats, one injection activates dopaminergic neurons in reward system of the abstinent rat (‘the first one is free’) • Stressful stimuli (e.g, non-dominant male, isolated rat) increases animal’s susceptibility to relapse

13. Sexual stimuli activate nodes of this limbic circuit (see note)(Dr. Anna Rose Childress, Penn) • Cue-induced cocaine craving activates limbic structures • correlated with subjective reports of craving

14. Treatment ‘Cold turkey’ method: Unnecessarily painful • Mimic the effect of the drug of addiction • The goal is to Minimize Withdrawal • Methadone (opioid) for heroin • Nicotine patch • Benzodiazepines (GABA) for alcohol • The new drug is less damaging • Problems: side effects, cost, social stigma • Block the drug • The goal is to counteract the drug of addiction • Problem: the lack of compliance due to withdrawal, disphoria, etc. • Cocaine ‘vaccine’ • Reduce addiction (tapping on the reward system) • Most promising approach (but untested)

15. - Commonly abused drugs: Write down as many as you can

16. Opiates: • Endogenous opiates: secreted in response to survival behaviors • analgesia • positive reinforcement (encourages the survival behavior) • Exogenous opiates; • Morphine (opium) • Codeine (opium) • Heroin (semisynthetic)

17. 1897 – Mail order advertisement from Sears, Roebuck & Co. for opium-based drink • Early 20th century – mothers encouraged to use opium syrup to soothe teething pain • Narcotic comes from the Greek word, “narke”, meaning stupor and referred to any drug that induced sleep

18. morphine Diacetyl-morphine (1898) Naloxone: Antagonist

19. Opiate Effects Analgesia Periaqueductal gray matter Blunted emotion to pain amygdala Euphoria limbic system Sedation reticular formation & locus coeruleus Reinforcement VTA and nucleus accumbens hypothermia hypothalamus (preoptic area) reduced libido reduced sexual hormones Autonomic effects brain stem Shallow breathing, Inhibit vomit*, Inhibit coughing Other effects: Small pupils, constipation, vasodilation (warm & flushed face)

20. Opiates: administration & distribution Administration: smoke (Opium, Heroin) intranasal (heroin) intravenous (Heroin) oral, not very good to get high (Codeine, morphine, methadone) Distribution: Heroin is 10 times more liposoluble than morphine, so it reaches brain faster and at larger concentrations, and get transformed into morphine

21. Opiates: tolerance & withdrawal Tolerance Develops rapidly (tenfold increase in 3-4 months) Shift from nasal to IV administration Withdrawal: due to increased noradrenaline by locus coeruleus starts 6-12 hs after last dosis, peaks at 48-72 hs, over after a week restless, agitation, chills, goose bumps (‘going cold turkey’), followed by drowsiness (12 hs), stomach cramps, vomit, diarrhea, sweating & twitching of extremities (‘kicking the habit’) Not as dangerous as alcohol withdrawal

22. Opiates: Side effects Most of the risks are secondary to the status as illegal. • Legal: Jail • Health: HIV, hepatitis C, overdose • Financial: loss of employment, cost of drugs • Few direct problems from chronic use (surprisingly) • (constipation, bladder cancer, pregnancy)

23. Opiates: Treatment • Acute overdose: • Naloxone (opiate antagonist) • Methadone maintenance (+ social support) • Potent opiate, but • Slow absorption (Oral administration) and thus • Blunted euphoric effect (No ‘high’) • Less addictive • Long-lasting (24hs half life): Blocks effect of heroin • Social support: • stable employment predicts clinical outcome • Shortcomings: • side effects, stigma, difficult access (6 states don’t have any clinic)

24. Opiates: treatment Medically supervised detoxification Goal: to block opioid receptors • Naltrexone (antagonist) • Buprenorphine: partial agonist (easier to detox than methadone) Problem 1: withdrawal Solution: Clonidine (alpha-2 adrenergic), antagonizes adrenergic response and thus minimizes withdrawal effects Problem 2: Relapses (?)

25. (Renton, the main character in the play, has decided to stop his heroin addiction, but wants a last hit) Renton: What the fuck are these? Mickey: Opium suppositories. Ideal for your purpose. Slow release. Bring you down gradually. Custom fucking designed for your needs. Renton: I want a fucking hit! (Renton voice over) Heroin had robbed Renton of his sex drive, but now it returned with a vengeance. And as the impotence of those days faded into memory, grim desperation took hold in his sex-crazed mind. His post-junk libido, fuelled by alcohol and amphetamine, taunted him remorselessly with his own unsatisfied desire dot. (22.00) Heroin makes you constipated. The heroin from my last hit is fading away and the suppositories have yet to melt. I am no longer constipated Trainspotting. Screenplay by John Hodge, based on novel by Irvine Welsh Maintenance Therapies Side effects of heroin Reduced libido Withdrawal: Diarrhea

26. Choose your future. Choose life. But why would I want to do a thing like that? I chose not to choose life: I chose something else. And the reasons? There are no reasons. Who need reasons when you've got heroin? People think it's all about misery and desperation and death and all that shite, which is not to be ignored, but what they forget - is the pleasure of it. Otherwise we wouldn't do it. After all, we're not fucking stupid. At least, we're not that fucking stupid. Take the best orgasm you ever had, multiply it by a thousand and you're still nowhere near it. When you're on junk you have only one worry: scoring. When you're off it you are suddenly obliged to worry about all sorts of other shite. …You have to worry about bills, about food, about some football team that never fucking winds, about human relationships and all the things that really don't matter when you've got a sincere and truthful junk habit. Trainspotting. Screenplay by John Hodge, based on novel by Irvine Welsh • Decision making: short-term vs. long-term reward • Reward system • Highjacked from natural reinforcers (e.g., sex, food)

27. The only drawback, or at least the principal drawback, is that you have to endure all manner of cunts telling you that … “ Every chance you've ever had, you've blown it, stuffing your veins with that filth” … He's always been lacking in moral fibre. • Moral model

28. Cocaine and Amphetamine: administration & distribution Administration: intranasal intravenous smoke (‘crack’) Distribution: ‘Crack’: is more liposoluble, thus stronger effect! Cocaine has a very short half life (40 mins)

29. Cocaine and Amphetamine • Dopamine agonists • Cocaine blocks dopamine reuptake • Amphetamine also stimulates dopamine release • Behavioral effects • Euphoria mesolimbic system (reward) • reinforce drug-taking behavior • Stimulation, Insomnia • repetitive motor behaviors nigrostriatal system • psychotic behavior: hallucinations, delusions of persecution • mood disturbances, • Chronic effect • decreased number of dopamine transporters in basal ganglia, despite a three year abstinence from the drug (predisposition to Parkinson’s disease)

30. Cocaine and Amphetamine: Treatment • Aimed at reducing ‘craving’ • Agonists on D3 receptors in reward system • GABA agonist to reduce dopamine secretion in reward system • Dopamine vaccine (?) • Antidepressants (?) • An effect of chronic cocaine use may be depression-like changes • Patients with Parkinson’s disease also have depression

31. Alcohol • Alcohol acts on many systems: • Blocks NMDA: that is why memory is impaired, and why alcohol withdrawal can trigger seizures • GABA: That is why at low levels alcohol has an anxiolytic effect, and at higher levels sedative effect • Dopamine (mesolimbic system): increases release of DA in nucleus accumbens, thus the euphoria, addictive power of alcohol

32. Alcohol • Fermentation (by yeast) • Sugar + water  alcohol + carbon dioxide (COs) • Grapes  wine • grains  beer • Yeasts tolerate only low levels of alcohol (10-15%) • Distillation • Alcohol + heat  vaporized alcohol • Wine  brandy • Fermented grains  whisky

33. Alcohol: Pharmacokinetics • Absorption is faster: • in empty stomach, because alcohol is metabolized in stomach • In high concentration (tequila vs. wine) • In women (lower levels of enzime in stomach) • Metabolization: • in the liver • 0.015% per hour (linear) • Nothing you can do to speed up rate • Blood Alcohol Concentration: • 0.08% (80 mg per 100 ml of blood) • > .08 illegal to drive • > .15 dangerous (black outs, unable to walk) • > .35 (1% death due to no gagging reflex)

34. Acute Alcohol Intoxication Blood Alcohol Concentration: 0.08% (80 mg per 100 ml of blood) Fatal Crashes: BACIncrease 0.05-0.09 11X 0.1-0.14 48X >0.15 380X (Zador, 1991)

35. Benzodiazepines • Mechanism of action • GABAergic system (major inhibitory system) • Effects: For treating: • Reduce anxiety phobias • Increase sleep (hypnotic), insomnia • Reduce seizures epilepsy, alcohol withdrawal • muscle relaxant cerebral palsy, pre-surgery • Side effects (same as before): • sedation, • drowsiness, • muscle weakness, • impair memory;

37. Benzodiazepines • Withdrawal (opposite of the main effects): • increased anxiety • insomnia, • tremor, • restlessness. • Peak in 2-10 days, and most think it abates within 4 weeks (others say it can take years).

38. Barbiturates • Mechanism of action • GABAergic system (major inhibitory system) • At higher (anesthetic) concentrations, they directly increase Cl- channel openings, even in the absence of GABA. • Rapid tolerance; • profound withdrawal; • low therapeutic index; • synergism with alcohol (Marilyn Monroe)

39. Nicotine • Mechanism of action • activates nicotinic receptors of acetylcholine (Ach) • Including those in the mesolimbic system • But unlike Ach, nicotine is not affected by Ach-ase • Steady concentration of nicotine in synapses leads to tolerance by down-regulation of receptors • Withdrawal: • Restlessness, anxiety, insomnia • Nicotine is highly addictive drug • Smokers exhibit compulsive behavior typical of drug addiction • it accounts for more deaths than the so-called “hard drugs”.

40. Cannabis: • THC is the active ingredient in marijuana. • THC receptor: CB1 • large concentration in hippocampus (memory effect) • THC stimulates release of dopamine in the nucleus accumbens and the ventral tegmental area • Long-term damage: • Cognitive impairments from long-term use appear to be subtle.