1. Causes of Alcohol Abuse and Alcoholism: Biological/Biochemical Perspectives

2. 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

3. 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?

4. 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

5. Brain Stimulation Reward (BSR)
BSR is intracranial self-stimulation
measure response rate of self stimulation
measure threshold current needed to sustain self-stimulation

6. 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.

7. 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

8. 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

9. 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

10. 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

11. 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?

12. 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

13. 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

14. 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

15. 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

16. Tolerance LS/SS tolerance differences P/NP differ in tolerance
Biochemical Differences
Probably some combination of known differences--see earlier slides

17. End

18. What About Humans?

19. 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

20. 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

21. 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

22. Potential Benefits of Genetic Research Programs
Important implications for:
Prevention
Early Detection
Treatment

23. Twin Studies: Concordance rates for DSM-III alcohol abuse/alcohol dependence among identical and fraternal twins.
Pickens et al (1991) “Heterogeneity in the inheritance of alcoholism. A study of male and
female twins.” Archives of General Psychiatry, 48, p19-28

24. 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

25. 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

26. 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

27. Identifying Markers of Inherited Resistance
Oriental Asian Flushing

28. 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