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

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 19 th 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 19 th – Treatment: decriminalize; total abstinence – Weakness of the model century, in ‘60s, and in AA : Addiction is not a ‘single’ disease

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).

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)

The Reward System:

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 Dopamine

Electrical intracranial self-stimulation

Olds & Milner (1954) 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 n. accumbens dopamine stimulation VTA

‘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

‘drug addiction is a learned pattern of behavior’

Brief detour on ‘Learning’: Classical conditioning

Pavlov’s dog: US  CS + US UR (meat -> salivate) (bell + meat) 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) CS  UR (bell -> salivate) CS & US are in close temporal proximity • Drugs with fast absorption are most addictive (close temporal link between behavior and drug effect)

Animals work for reinforcement for several reasons, including...

operant conditioning Classical conditioning

Dopamine release in the nucleus accumbens

during Intracranial self stimulation -during ingestion of a preferred food - to a cue associated with food (CS) - during sexual behavior - in anticipation of sex -during IV cocaine self-administration -to a cue associated with cocaine (CS)

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)

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

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

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)

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

Opiates:

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

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

morphine Naloxone: Antagonist Diacetyl-morphine (1898)

Opiate Effects

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

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

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

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)

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)

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 (?)

Trainspotting. Screenplay by John Hodge, based on novel by Irvine Welsh

Maintenance Therapies (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!

Side effects of heroin Reduced libido (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) Withdrawal: Diarrhea 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 Decision making: short-term vs. long-term reward 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? Reward system Highjacked from natural reinforcers (e.g., sex, food) 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.

Moral model 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.

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)

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 – psychotic behavior: hallucinations, delusions of persecution – mood disturbances, nigrostriatal system Chronic effect – decreased number of dopamine transporters in basal ganglia, despite a three year abstinence from the drug (predisposition to Parkinson’s disease)

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

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

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

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)

Acute Alcohol Intoxication

Blood Alcohol Concentration: 0.08% (80 mg per 100 ml of blood)

Fatal Crashes:

BAC 0.05-0.09

0.1-0.14

>0.15

(Zador, 1991) Increase 11X 48X 380X

Benzodiazepines

Mechanism of action

– GABAergic system (major inhibitory system)

Effects:

– Reduce anxiety – Increase sleep (hypnotic), – Reduce seizures – muscle relaxant Side effects (same as before): – sedation, – drowsiness, – muscle weakness, – impair memory;

For treating

phobias insomnia : epilepsy, alcohol withdrawal cerebral palsy, pre-surgery

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).

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)

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”.

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.