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Neurobehavioral Aspects of Alcohol Consumption
Source: Eighth Special Report to the U.S. Congress on Alcohol and Health
Secretary of Health and Human Services
September, 1993
pp 113-128
Alcohol-Seeking Behavior and the Development of Chronic Drinking• Physical Dependence
– tolerance– withdrawal– cause or consequence?
• Psychological Dependence– compulsive craving– drinking independent of physical dependence and
withdrawal• A fundamental question is: Are the reported
pleasure sensations that lead to alcohol-seeking due to its euphoric effect, or to the reduction of some underlying anxiety?
Reinforcement
• Reinforcement is the process whereby the probability of a response is increased if it results in a particular effect
• positive reinforcement– learned behavior to achieve a reward
• negative reinforcement– learned behavior to avoid discomfort
Brain Stimulation Reward (BSR)• BSR is intracranial self-stimulation
– measure response rate of self stimulation
– measure threshold current needed to sustain self-stimulation
Alcohol’s Effects on Brain Stimulation Reward (BSR)
• Rat response rates increased during BAC rise; no effect during BAC drop phase
• Thought to be analogous to human sensations of pleasure and euphoria during BAC rise.
Biphasic Action of Alcohol:Stimulation(low BAC) then
Sedation (high BAC)
• Low doses stimulate “Spontaneous Motor Activity” (SMA) in rats during rising BAC
• High doses give sedation and sleep• SMA stimulation occurs through elevating
dopamine levels in ventral tegmental area of the brain (nucleus acumbens reward center)
• These changes are correlated with the enhancement of the brain stimulation reward threshold
Neurochemical Mechanisms of Alcohol Reinforcement
• Dopamine– alcohol and cocaine stimulate concentrations in
nucleus acumbens and other reward centers– Dopamine antagonists increase alcohol intake
in rats, e.g.., more alcohol is required to achieve pleasurable response
– Dopamine agonists decrease alcohol intake in rats , e.g.., less alcohol is required to achieve pleasurable response
Neurochemical Mechanisms of Alcohol Reinforcement
• Serotonin– alcohol increases serotonin concentrations in
certain regions of the brain– brain of alcohol preferring rats contain lower
concentrations of serotonin than wild type rats.– Serotonin agonists reduce alcohol intake
Neurochemical Mechanisms of Alcohol Reinforcement
• Endogenous Opiates– alcohol stimulates release of enkephalins and
endorphins…producing euphoria and pain attenuation
– Opiate receptor antagonists reduce the reinforcing effects of alcohol
Genetic Evidence of the Biological Basis for Problem Drinking -- Animal Models
Are there demonstrable genetic differences (biological differences) that might make some individuals more prone to alcohol-seeking behavior?
Are some individuals less likely to experience withdrawal? Tolerance? What is the genetic evidence that such traits are inherited and thus based in biological difference?
Alcohol Seeking Behavior
• Alcohol Preferring (P) and Alcohol non-Preferring (NP) Rats– bred through repeated
generations to maximally exhibit this behavior
– P rats will do anything to get alcohol -- very strong positive reinforcement -- despite harm
• Fast/Slow SMA Mice– Fast mice quickly
respond to stimulatory effects of alcohol
– Slow mice do not respond initially to the stimulatory effect
– Slow mice develop tolerance to depressive effect after 31 days and then are Stimulated
Molecular Biol. Properties of P/NP
• P/NP have comparative differences in LTW-4 protein
• LTW-4 Protein increases in both P and NP with increased alcohol consumption
Sensitivity to Sedative Properties of Alcohol
• Long-Sleep/Short-Sleep mice– differ by righting reflex
– LS loose righting reflex with 1/2 the alcohol level of SS
– LS looses righting reflex with 1/30 the alcohol when admin. to Purkinge cells
• Biochemical Differences– LS more sensitive to
alcohol augmentation of GABA function
– GABA receptor in LS mice has enhanced alcohol activation
Differences in Withdrawal/Dependence
• Withdrawal-Seizure Prone(WSP) and Withdrawal-Seizure Resistant(WSR) mice– 10x more severe
symptoms– no difference in
sensitivity to other affects of alcohol including tolerance
• Biochemical Differences– Must be Genetic
Component to Dependence
– Glutamate receptors increase with alcohol consumption
– WSP have more hippocampal NMDA (glutamate) receptors
Tolerance
• LS/SS tolerance differences
• P/NP differ in tolerance
• Biochemical Differences– Probably some
combination of known differences--see earlier slides
Genetic Evidence from Animal Models for a Biological Cause of
Problem Drinking
• P rats “Alcohol Preferring”
• NP rats “Alcohol Avoiding”
• Fast “Spontaneous Motor Activity” mice
• Slow “Spontaneous Motor Activity” mice
Suggestive Trends
• 80% of alcoholics in inpatient treatment have close relative with an alcohol problem
• Seven times greater risk among first-degree relatives of alcoholics than that of the general population
Goals of Genetic Investigations
• Detect and Quantify effects of Genetic Determinants on Problem Drinking
• Characterize Patterns of Inheritance• Identify Genes that Confer Vulnerability• Identify Factors other than Genes that affect
pathogenesis of alcoholism• Locating Specific Genes on the Genome
that Confer Susceptibility
Potential Benefits of Genetic Research Programs
• Important implications for:– Prevention– Early Detection– Treatment
Twin Studies: Concordance rates for DSM-III alcohol abuse/alcohol dependence among identical
and fraternal twins. Male Subjects Female SubjectsDiagnosis
Identical Fraternal Identical Fraternal
Alcoholabuse and/oralcoholdependence
0.76 0.61 0.36 0.25
Alcoholdepencence
0.59 0.36 0.25 0.05
Pickens et al (1991) “Heterogeneity in the inheritance of alcoholism. A study of male andfemale twins.” Archives of General Psychiatry, 48, p19-28
0.36 0.250.76 0.61
0.59 0.36 0.25 0.05
Swedish Adoption Studies• Incidence of Alcohol Problem among
genetically unrelated individuals in same home environment– 2.5 fold increased risk for children of Alcoholic
Parent– Type I -- most common, mild, adult onset,
dependent on environment– Type II -- less comon, severe, in men, early
onset, agressive behavior– Type III -- like Type II but lacks agressive
behavior
Biochemical Risk Markers
• Genes for serotonin transporter• Gene variant for GABA receptor • Gene for catechol-O-methyltransferase (enzyme
for dopamine metabolism) Variant leading to increased susceptibility to pain and anxiety also high risk for alcohol problems
• Variants of the μ-opioid receptor determine whether naltrexone is effective or not in treatment of alcoholism
Identifying Markers of Inherited Vulnerability
• Electrophysiology Markers• Biochemical Markers
– platelet monoamine oxidase and adenylate cyclase activities
– rate of platelet serotonin uptake
• Differences in Reactions to Alcohol– Low response to alcohol
– alcohol-induced increase in baseline heart rate
– alcohol-induced decreases in plasma prolactin and cortisol