Genetic and Other Risk Factors for Alcoholism and Alcohol Abuse. Manzardo, Ch 11,12 Fingarette, pp 51-55
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1 Genetic and Other Risk Factors for ism and Abuse Manzardo, Ch 11,12 Fingarette, pp 51-55
2 Suggestive Trends 80% of alcoholics in inpatient treatment have close relative with an alcohol problem Five times greater risk among first-degree relatives of alcoholics than that of the general population ic Parents 25% of sons and 5-10% of daughters become alcoholic General Population 5% of sons and 1% of daughters
3 Objectives 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 pathogenisis of alcoholism Examine interaction between genetic factors and environment
4 Experimental Designs to Study Genetic/Environmental Factors among Twin and Non-Twin Siblings
5 Twin Studies: Concordance rates for DSM-III alcohol abuse/alcohol dependence among identical and fraternal twins. Diagnosis Male Subjects Female Subjects Identical Fraternal Identical Fraternal abuse and/or alcohol dependence depencence Pickens et al (1991) Heterogeneity in the inheritance of alcoholism. A study of male and female twins. Archives of General Psychiatry, 48, p19-28
6 Twin Studies: Concordance rates for DSM-III alcohol abuse/alcohol dependence among identical and fraternal twins. Diagnosis Male Subjects Female Subjects Identical Fraternal Identical Fraternal abuse and/or alcohol dependence depencence Pickens et al (1991) Heterogeneity in the inheritance of alcoholism. A study of male and female twins. Archives of General Psychiatry, 48, p19-28
7 Twin Studies: Concordance rates for DSM-III alcohol abuse/alcohol dependence among identical and fraternal twins. Diagnosis Male Subjects Female Subjects Identical Fraternal Identical Fraternal abuse and/or alcohol dependence depencence Pickens et al (1991) Heterogeneity in the inheritance of alcoholism. A study of male and female twins. Archives of General Psychiatry, 48, p19-28
8 Twin Studies: Concordance rates for DSM-III alcohol abuse/alcohol dependence among identical and fraternal twins. Diagnosis Male Subjects Female Subjects Identical Fraternal Identical Fraternal abuse and/or alcohol dependence depencence Pickens et al (1991) Heterogeneity in the inheritance of alcoholism. A study of male and female twins. Archives of General Psychiatry, 48, p19-28
9 Twin Studies: Concordance rates for DSM-III alcohol abuse/alcohol dependence among identical and fraternal twins. Diagnosis Male Subjects Female Subjects Identical Fraternal Identical Fraternal abuse and/or alcohol dependence depencence Pickens et al (1991) Heterogeneity in the inheritance of alcoholism. A study of male and female twins. Archives of General Psychiatry, 48, p19-28
10 Swedish Adoption Studies Incidence of Problem among genetically unrelated individuals in same home environment 2.5 fold increased risk for children of ic 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
11 Animal Models
12 Seeking Behavior Preferring (P) and 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 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 variant present in P LTW-4 Protein increases in both P and NP with increased alcohol consumption
14 Response to Sedation Effects of 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 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 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-induced increase in baseline heart rate alcohol-induced decreases in plasma prolactin and cortisol
18 Temperament and Behavior Risk Factors hyperactivity hyperactivity and aggression low attention span high task persistence labile emotional expressivity low ability to calm oneself following stress facile social behavior
19 Potential Benefits of Genetic Research Programs Important implications for: Prevention Early Detection Treatment
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