Clinical-Genetic Variation in GABA /Alcohol Sensitivity

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DESCRIPTION (provided by applicant): NIAAA is dedicated to understanding the genetic factors that increase vulnerabilIty to alcoholism. Previous research has suggested that children of alcoholic fathers are at increased risk, perhaps because of a reduced or altered sensitivity to the effects of alcohol. A functional polymorphism of the GABA-A receptor a6 gene has been identified as a plausible cause for reduced sensitivity to motor impairment by alcohol or benzodiazepines. The polymorphism is a Proline to Serine amino acid substitution at position #385 (i.e., Pro385Ser). This is a revised R21 application that, in response to previous review critiques, has narrowed the focus of this exploratory study to more certainly address the role of the Pro385Ser a6 polvmorphism in conferring an altered drug response to positive modulators of the GABA-A complex in the children of alcoholic fathers who have not yet exhibited alcohol abuse or dependence. The proposal applies a human pharmacogenetic approach to experimentally test the hypothesis that within the population of male and female social drinkers aged 21-25 years who are presumed at risk for alcoholism because of a Family History of paternal alcoholism, there remain differences in sensitivity to motor impairment from alcohol and benzodiazepines that can be accounted for by the presence of the Pro385Ser polymorphism. Furthermore, we will explore whether this reduced impairment also may be associated with reduced self-reports of intoxication or enhanced euphoric or reinforcing effects. Participants who are social drinkers without a DSM- IV, Axis-I diagnosis, will be selected into two groups based upon whether they are homozygous (Pro/Pro) or heterozygous (Pro/Ser) for the serine-substituted allele (Pro385Ser) of the a6 subunit. In a 2x5 factorial mixed-model ANOVA design, participants from each of these groups will be tested in a crossover study administering challenge doses of placebo, ethanol, and triazolam in a laboratory environment where subjective, motor, and behavioral responses can be repeatedly assessed using standard techniques with which the investigators have a great deal of experience. This study will substantially extend our knowledge of functional differences in the pharmacodynamic effects of GABA-A positive modulators that may be attributable to the a6 polymorphism or other associated genes co-occurring within the same chromosomal cluster.