Transcript Overview of Neurobiology of Addiction

Alcohol:
Pharmacology and Neurobiology
Vijay A. Ramchandani, Ph.D.
Indiana University School of Medicine
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Outline
• Pharmacokinetics
– Absorption
– Distribution
– Metabolism
• Pharmacodynamics
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CNS effects
Tolerance
Alcohol as a reinforcer
Neuropharmacological effects
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Pharmacokinetics: Absorption
• Rapidly absorbed primarily from duodenum
• Rate of absorption is extremely variable
• Peak blood alcohol concentration (BAC) depends on:
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–
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Amount and alcohol concentration of beverage
Rate of drinking
Food consumption and composition
Gastric emptying and gastric metabolism
Hepatic first pass
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Distribution
• Volume of distribution = Total Body Water
• Gender Differences in body composition
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Metabolism
• Metabolism
– 90-98% metabolized in liver
Alcohol
Alcohol
dehydrogenase
Acetaldehyde
Aldehyde
dehydrogenase
Acetate
– Alcohol dehydrogenase saturates at low to moderate BACs
(Michaelis-Menten kinetics)
– Apparent zero-order kinetics at moderate BACs
• Alcohol Elimination Rate = 7 g per hr
• Disappearance Rate = 0.015% per hr
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Metabolism
• Metabolism
Alcohol
Alcohol
dehydrogenase
Acetaldehyde
Aldehyde
dehydrogenase
Acetate
– Aldehyde dehydrogenase usually not rate-limiting
– Accumulation of acetaldehyde associated with headache,
gastritis, nausea, dizziness (hangover)
– Aldehyde dehydrogenase inhibition (disulfiram)
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Metabolism: Genetic Variation
Genetic variation in alcohol metabolizing enzymes
• Alcohol Dehydrogenase (ADH)
– Polymorphism occurs at ADH2 and ADH3 loci
White American
Black American
Asian
ADH2*1
95%
85%
15%
ADH2*2
<5%
<5%
85%
ADH2*3
<5%
15%
<5%
ADH3*1
50%
85%
95%
ADH3*2
50%
15%
5%
– 15% of Black Americans have ADH2*3 allele  increased alcohol metabolic rate
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Metabolism: Genetic Variation
Genetic variation in alcohol metabolizing enzymes
• Aldehyde Dehydrogenase (ALDH)
– Polymorphism at the ALDH2 gene
• 50% of Asians have ALDH2*2 allele
 decreased elimination of acetaldehyde (and alcohol)
 flushing response
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Pharmacokinetics: Gender Differences
• Gender Differences
– in absorption
• Differences in gastric ADH activity
– in volume of distribution
• Differences in body composition and total body water (TBW)
– in metabolism
• Differences in liver volume, ADH activity?
• Effect of menstrual cycle on alcohol pharmacokinetics
• Effect of sex hormones (OC) on alcohol PK
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Pharmacodynamics: CNS Effects
• Alcohol is a CNS depressant
• Apparent stimulatory effects result from depression of
inhibitory control mechanisms in the brain
• Characteristic response: euphoria, impaired thought
processes, decreased mechanical efficiency
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Concentration-Effect Relationship
BAC [%]
Effects
0.02-0.03
Mood elevation. Slight muscle relaxation.
0.05-0.06
Relaxation and Warmth. Increased reaction time. Decreased
fine muscle coordination.
0.08-0.09
Impaired balance, speech, vision, hearing, muscle coordination.
Euphoria.
0.14-0.15
Gross impairment of physical and mental control.
0.20-0.30
Severely intoxicated. Very little control of mind or body.
0.40-0.50
Unconscious. Deep coma. Death from respiratory depression
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Tolerance: Definitions
• Tolerance: The phenomenon of decreased effect with
prolonged exposure to a drug
• Acute tolerance: during the time-course of a single
exposure to drug
• Chronic tolerance: over repeated use of drug
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Tolerance: Significance
• Why is tolerance to alcohol important?
– One of the determinants of increased alcohol consumption
• maintains or aggravates alcohol dependence
• increases risk of organic complications of alcoholism
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Diagnostic criteria for alcoholism by DSM-IV
Cross-tolerance to other depressant drugs
Genetic determinants exist
Low Response predicts alcoholism
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Alcohol as a Reinforcer
• Reinforcer: a substance whose pharmacological effects
drive the user to continue to use it.
• Positive reinforcing effects:
– Gain pleasure
– Altered consciousness
– Conform to behavior of peers
• Negative reinforcing effects:
– Relief of stress and negative emotions
– Relief of withdrawal symptoms
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Alcohol as a Reinforcer: Neural Systems
Activation of mesocorticolimbic system
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Alcohol as a Reinforcer: Evidence
• Animal models of alcohol preference
– Selectively bred animal lines show innate differences in limbic
structures and neurotransmitter function
• Animal models of self-administration
– Animals trained to chronically self-administer alcohol show
differences in neurotransmitter levels in the mesolimbic system
– Animals will bar-press repeatedly for intra-cranial injections of
alcohol into the VTA
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Reinforcement: Neurochemical systems
Enkephalin or
Dynorphin
Inhibitory Neuron
Glutamate
Excitatory Input
k Opioid
Receptors
Enkephalin
Inhibitory
Neuron
Dopamine Receptors
Dopamine Neuron
m Opioid
Receptors
GABA
Neuron
REWARD
GABA-A Receptors
GABA Inhibitory Feedback
GABA
Inhibitory
Neuron
Presynaptic
Opioid
Receptors
(m, d?)
Ventral Tegmental Area
(VTA)
Nucleus Accumbens
(NAc)
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Neuropharmacology: GABA
• Effects on GABA system
– Interaction with GABA-A receptor and facilitation of GABA
transmission
• Sedative and anxiolytic effects
• Withdrawal
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Neuropharmacology: DA, Opioids
• Effects on Dopamine system
– Increase dopamine in mesocorticolimbic system
• Reinforcing, rewarding effects
• Effects on Opioid peptide system
– Activation of opioid peptide system
• Reinforcing and rewarding effects (Mu)
• Aversion (Kappa)
• Craving
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Neuropharmacology: NMDA, 5HT
• Effects on NMDA Glutamate system
– Blockage of NMDA receptor (allosteric effect)
• Sedative/hypnotic effects
• Neuroadaptation
• Withdrawal
• Effects on Serotonin system
• Neuroadaptation, aversion
• Effects on stress hormones
• Stress response
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Neuropharmacology: Summary
Experience
euphoria/pleasure
anxiolysis/ataxia
sedation/amnesia
nausea
neuroadaptation
stress
withdrawal
Transmitter/Receptor
Dopamine, Opioids
 GABA
 GABA +  NMDA
5HT3
NMDA, 5HT
CRF
GABA, NMDA ( Ca, Mg)
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Implications for Pharmacotherapy
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Disulfiram
Naltrexone
Acamprosate
Benzodiazepines
SSRIs
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