Download EtOH DEPENDENT CONTROL

CM 16- Neurobiology of Addiction
DSM-IV Criteria Substance Abuse
• A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by
one or more of the following occurring within a 12 month time period:
• Failure to fulfill role obligations (absences or poor work, absences or poor performance at school,
suspension; failure to care for children)
• Recurrent use in physically hazardous situations (driving, operating machinery)
• Recurrent legal problems (arrests for substance related problems, DUI, possession)
• Continuing to use despite social or interpersonal problems. (Recurrent arguments with family members
about intoxication)
Current Theory: Reward Pathway
• There is a reward pathway in the brain which is activated by
• Food, water and sex
• Nurturing and caring for others
• “Thrills” (hang gliding, merry-go-rounds)
• Exercise
• This reward pathway is also activated by
• Drugs, including alcohol
• Gambling
Neurotransmitters and anatomical sites involved in the acute reinforcing effects of drug abuse
• Dopamine: Ventral tegmental area, nucleus accumbens
Function: pleasure, euphoria, mood, motor function
Receptors: D1, D2
• GABA: Amygdala, nucleus of stria terminalis (causes anxiety)
• Opioid Peptides: Nucleus accumbens, amygdale, ventral tegmental area
• Glutamate: nucleus accumbens
Neuropeptides that activate receptors and act on reward pathway
• Cannabinoids: pain, appetite, memory
Receptors: CB1, CB2
• Serotonin: mood, impulsivity, anxiety, sleep, cognition
Receptors: 5HT3
• Opioid peptides (Endorphins, Enkephalins): pain
Receptors: Kappa, Mu, Delta
In all rewards, dopamine is the final activation chemical
Stimulation of the Ventral Tegmental Area (VTA) or nucleus accumbens
• Reward Center of Brain: Took a mouse and implanted indwelling electrode in the VTA and hooked up the
stimulus of this to a press bar.
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Every time little mouse pressed the bar, he got a microstimulation of electricity in the VTA. When you put a
mouse in this apparatus, he will randomly flail until he hits the bar, and gradually he will discover that pressing
the bar is correlated with this pleasure.
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He will press the bar until he collapses, wakes up, press, press (no food no water no sex), death.
• What happens if you cut the pathway from VTA to Forebrain (median forebrain bundle)? : The mouse gives up
pressing the bar.
CM 16- Neurobiology of Addiction
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Evidence for reward pathway
Stimulation (electrical or chemical) of nucleus accumbens & VTA is intrinsically rewarding.
• Stimulation elsewhere is not
Reward can be interrupted by
• Severing nucleus accumbens-frontal cortex fibers
• Using dopamine blocker
Blocking can interrupt naturally rewarded behaviors
• Patients on drugs that block dopamine “look flat” and experience decreased emotions
• Human addicts ignore daily vegetative behaviors. Compulsive use in spite of consequences, ignoring
other roles once important to them.
• How can a pregnant woman use drugs? She ignores even basic human instinct to protect her offspring
and gets reward of drug
Dopamine is the primary transmitter that is the final activation chemical in all rewards
Activates D1 receptors
• D1 is primarily involved in addiction and in the human sense of pleasure
• D2 receptors are also activated (involved in psychosis)
• Responsible for reinforcing behavior
Development of Addiction
The use of the drug of abuse is increased to maintain euphoria or to avoid dysphoria or withdrawal symptoms
The number of receptors gradually increases to counter for the continual presence of the drug of abuse
The amount of neurotransmitter gradually decreases through depletion and feedback inhibition
The reinforcing properties of the drug are thus gradually decreased (tolerance)
The need for drug to maintain this new homeostasis is therefore increased (dependence begins)
Natural Rewards: Dopaminergic Involvement
Food
Sex
CM 16- Neurobiology of Addiction
Drugs of Abuse: rodent self-administration
Amphetamine
Cocaine
Nicotine
Ethanol
Direct Action
Some of the actions of drugs of abuse are due to direct action on a psychoactive receptor
• Example: opioid (pain medications) binding to mu or endorphin receptors
• Effect limited by the number of receptors present
• Direct action continues as long as drug is present
• Opiates/Opioids ( like heroin, morphine) increase the activity of dopaminergic neurons in the VTA by
inhibiting GABA-ergic interneurons that normally exert an inhibitory effect on them
The drug dominates control of the reward center
Continued use of opiates makes the body rely on the presence of the drug to maintain rewarding feelings and other
normal behaviors.
The person is no longer able to:
• feel the benefits of natural rewards (food, water, sex)
• can't function normally without the drug present.
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Indirect action
1. Indirect action on a given transmitter system
• Serotonergic effect of alcohol via G coupled protein receptors
• Use of secondary messenger systems
2. Indirect action via a neurotransmitter which in turn modulates another transmitter system
Alcohol as an example:
• Binds to receptors
• GABAA : Enhances the activity of GABA on cells: alcohol is a sedative, anxiolytic, and affects balance and
coordination via this mechanism
• NMDA subtype of the glutamate receptor: important in initial stages of memory formation, neural
excitability , excitotoxic brain damage and neural development. EtOH is a potent inhibitor of NMDA
receptor, esp. at lower concentrations of alcohol like 50 mg (1-2 drinks). Causes sedation, memory
blackout, and has anxiolytic effect
• Potentiate Acetycholine at nicotinic cholinergic receptors
• Mu: low to moderate does of alcohol promote binding of mu agonists at mu receptor, which are present
on cell bodies in the VTA ; activation of these receptors causes release of dopamine.
• mu receptor antagonist, naltrexone, blocks the craving for alcohol in some drinkers
• Endorphin
• Activates receptor-coupled adenylcyclase systems.
• Downstream effects on dopamine from above systems
• Even though alcohol does not directly cause release of dopamine ( like cocaine does) it acts downstream
via other receptors and neurotransmitters.
• In high doses affects membrane lipids
CM 16- Neurobiology of Addiction
Cocaine
• Act via reuptake inhibition of dopamine
• Promote dopamine release via dopamine transporter
• Because indirect action depends on existing neurotransmitter, effect of drug attenuates as this is depleted
• If dopamine is dumped into the extracellular space repeatedly, and once dopamine is depleted from the
cell, the individual is no longer able to get the rush or high
• Dopamine sensitization is a bit more complex and is the result of repeated exposure: the binge-crash
cycle. Occurs in the nucleus accumbens
Drug Action and Reward Pathway
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Withdrawal from alcohol and drugs
Tolerance: a physiologic adaptation of the organism to the presence of a drug.
Withdrawal is the result of an abrupt cessation of the drug. Withdrawal syndrome involves:
• activation of the thalamus
• release of corticotrophin releasing factor (CRF)
• disturbance of the autonomic nervous system
• activation of the locus coeruleus
• Locus coeruleus has projections to frontal cortex, limbic cortex, and amygdala
• Individual feels dysphoric, depressed, angry, and irritable due to withdrawal
Increased: HR, BP, blood glucose, response
to stressors
CRF System mediates the affective and somatic symptoms of drug withdrawal
CM 16- Neurobiology of Addiction
Extracellular Corticotrophin Releasing Factor levels in the amygdala during withdrawal from ethanol
Withdrawal: DA and 5-HT Involvement
Extracellular DA and 5-HT in the Nucleus Accumbens During Cocaine Self-Administration and Withdrawal
Intoxication and Withdrawal: Neurotransmitter Involvement
Pt feels dysphoric, irritable,
depressed and angry
CM 16- Neurobiology of Addiction
Molecular Mechanisms
Alcohol: representation of GABA receptor sensitivity
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Treatment of Addiction
Alcohol dependence:
Naltrexone: blocks mu opioid receptor (reduces the rewarding effects of alcohol)
Acamprosate: inhibits the release of glutamate thus decreasing excitation (withdrawal) that occurs
during withdrawal
Disulfiram: deterrant- causes building up of acetaldehyde, leading to severe vomiting flushing of the
skin, accelerated heart rate, shortness of breath, nausea, vomiting, throbbing headache, visual
disturbance, mental confusion, postural syncope, and circulatory collapse
Tobacco dependence:
Nicotine gum/patch: activate nicotinic receptors
Bupropion- inhibits reuptake of dopamine, noradrenaline, and serotonin in the central nervous
system, is a non-competitive nicotine receptor antagonist, and at high concentrations inhibits
the firing of noradrenergic neurons in the locus caeruleus.
Psychostimulant dependence:
Rimonabant: blocks cannabinoid receptors (CB)- not available
Heroin dependence:
Methadone, Buprenorphine: activate opioid receptors