Transcript Alcohol Effects on Inhibitory Mechanisms of Visual Attention

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 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
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)
Dopamine
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
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.
dopamine
(Satan, in John Milton’s Paradise Lost, book 1, ll. 254–5)
Quoted by R. Cardinal
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  UR (meat -> salivate)
CS + US (bell + meat)
CS  UR (bell -> salivate)
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
CS & US are in close temporal proximity 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 sexual behavior
- in anticipation of sex
-during ingestion of a preferred food
- to a cue associated with food (CS)
-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 opiumbased 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
morphine
Diacetyl-morphine (1898)
Naloxone:
Antagonist
Opiate Effects
Analgesia
Blunted emotion to pain
Euphoria
Sedation
Periaqueductal gray matter
amygdala
limbic system
reticular formation & locus coeruleus
Reinforcement
VTA and nucleus accumbens
hypothermia
reduced libido
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
Side effects of heroin
Reduced libido
Withdrawal: Diarrhea
(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 postjunk 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
Decision making:
short-term vs.
long-term reward
Reward system
Highjacked from
natural reinforcers
(e.g., sex, food)
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.
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
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)
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
Increase
0.05-0.09
11X
0.1-0.14
48X
>0.15
380X
(Zador, 1991)
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 downregulation 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.