The gamma-aminobutyric acid type A receptor (GABAA-R) has been extensively implicated as a key component of the mechanism of action of ethanol. However, the contribution of individual subunits of the GABAA-R to ethanol-related behaviors has not been adequately addressed. The alpha4 subunit of the GABAA-R has specifically been implicated in modulating behavioral hyperexcitibility in a variety of experimental conditions including ethanol dependence and withdrawal. The use of sophisticated transgenic and gene targeting technology now allows hypotheses to be tested in an unambiguous manner, using precise molecular tools within the context of the whole animal. By testing a variety of mouse models with altered regional and temporal patterns of expression of alpha4 on a battery of molecular, cellular, and behavioral assays, we have the opportunity to elucidate the contribution of the alpha4 subunit to clinically relevant ethanol-related behaviors. We believe these studies provide an integrated approach toward our goal of understanding how ethanol exerts its effects in the central nervous system. To accomplish our goal, the following specific aims are proposed: A1. Create and characterize a transgenic mouse line that overexpresses a tetracycline regulated GABAA-R alpha4 subunit. A2. Create and characterize genetically engineered mice that harbor a ubiquitous knockout of the alpha4 subunit of the GABAA-R. A3. Create and characterize novel transgenic mouse lines that direct inducible, neuron-specific gene recombination. A4. Create and characterize an inducible, neuron-specific GABAAR alpha4 knockout mouse line. A5. Analyze these genetically manipulated animals with a battery of tests to assess basic physiology, behavior, and phenotypic alterations in ethanol-induced behaviors.
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