Alcoholism is a complex disease that has both environmental and genetic determinants. The identification of the genes that predispose an individual to alcoholism is difficult due to genetic heterogeneity within the human population. Animal models (e.g. inbred mice) offer an alternative approach to identify genes that influence the susceptibility to alcoholism because mice and humans share largely conserved chromosomal regions. DBA/2J (D2) and C57BL/6J (B6) inbred mouse strains are well-characterized models of severe vs. mild acute ethanol withdrawal. The GABAA receptor gamma2 subunit gene (Gabrg2) is polymorphic between the D2 and B6 strains. In this proposal, we will test the hypothesis that genetically determined differences in acute ethanol withdrawal severity are due, at least in part, to Gabrg2 variation. We will assess Gabrgl mRNA content in congenic, D2 and B6 strains to test the hypothesis that increased acute ethanol withdrawal severity is associated with decreased mRNA content. We will also test the effect that this polymorphism has on GABAA receptor function/subunit assembly by examining 36Cl- influx in membrane vesicles prepared from discrete brain regions in the same populations of mice. Lastly, we will also address the hypothesis that different Gabrg2 allelic dosages affects acute ethanol withdrawal severity by assessing mice that have a hemizygous deletion of Gabrg2. These studies will help provide the foundation for future studies investigating how genetic variation regulates alcohol abuse and alcoholism.
