Causes of Alcohol Abuse and Alcoholism:

Biological/Biochemical Perspectives

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

End

What About Humans?

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

Identifying Markers of Inherited Resistance

• Oriental Asian Flushing

Temperament and Behavior

• hyperactivity

• hyperactivity and aggression

• low attention span

• task persistence

• labile emotional expressivity

• slow ability to calm oneself following stress

• facile social behavior