Drug Abuse: Outline

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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

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Models of AddictionWhy 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

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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 itwant it so
  bad you can almost taste it ...but you aint sick
  ...sick is, well sick" (Childress et al.1988).

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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)

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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
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Electrical intracranial self-stimulation
stimulation

• Olds Milner (1954)

n. accumbens
The mind is its own place, and in itself, can
make heaven of Hell, and a hell of Heaven.
(Satan, in John Miltons Paradise Lost, book 1,
ll. 2545) Quoted by R. Cardinal
VTA
dopamine
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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
Skinners box
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drug addiction is a learned pattern of behavior
Brief detour on Learning Classical conditioning
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Animals work for reinforcement for several
reasons, including...

operant conditioning
Classical conditioning
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Dopamine release in the nucleus accumbens
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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)

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• 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 animals susceptibility
  to relapse

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• 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

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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)

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

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

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• 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

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morphine
Diacetyl-morphine (1898)
Naloxone Antagonist
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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)

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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

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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

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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)

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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
  dont have any clinic)

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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 (?)

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

• (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

Maintenance Therapies Side effects of
heroin Reduced libido Withdrawal Diarrhea
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Trainspotting. Screenplay by John Hodge, based on
novel by Irvine Welsh

• 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.

• Decision making short-term vs. long-term reward
• Reward system
• Highjacked from natural reinforcers (e.g., sex,
  food)

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• 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

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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)

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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 Parkinsons
  disease)

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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 Parkinsons disease also have
  depression

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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

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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

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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)
• gt .08 illegal to drive
• gt .15 dangerous (black outs, unable to walk)
• gt .35 (1 death due to no gagging reflex)

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Acute Alcohol Intoxication
Blood Alcohol Concentration 0.08 (80 mg per 100
ml of blood)
Fatal Crashes BAC Increase 0.05-0.09 11X 0.1
-0.14 48X gt0.15 380X (Zador, 1991)
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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

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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).

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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)

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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.

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• 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.