Causes of Alcohol Abuse and Alcoholism: Biological/Biochemical Perspectives

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 113-128

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 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 Alcohol Seeking Behavior

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. 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 Sensitivity to Sedative Properties of Alcohol

15. 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 Differences in Withdrawal/Dependence

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

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. 0.76 0.61 0.36 0.25 0.59 0.36 0.25 0.05 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