This project applies genetic dissection of putative molecular targets of ethanol to explain the neurophysiologic basis of ethanol action. We hypothesize that specific subunits of brain type gamma aminobutryic acid receptors (GABAA-RS) mediate specific behavioral responses to ethanol, as demonstrated for benzodiazepines and intravenous anesthetics. Our work during the previous funding period has (a) provided novel insight into ethanol action, (b) revealed shortcomings of traditional global gene knockout technology, and (c) has demonstrated the promise that conditional knockout and knockin technologies can deliver. The gene knockin and the conditional knockout approaches provide tools to test the GABA hypothesis of alcohol action that are not limited by the problems that plague the global knockout approach. We now propose to analyze genetically engineered mice that harbor ethanol-insensitive, but otherwise normal GABAA-R subunits. GABAA-R mutant mice will be analyzed with a battery of tests that span the molecular, cellular, and behavioral levels. Such a multi-level approach allows a determination of the relevance of a specific drug target (receptor) as a mediator of a specific phenotype (e.g., motor ataxia). These studies could define molecular targets of ethanol action that are responsible for specific clinically relevant behavioral responses. Ultimately that knowledge could lead to novel therapeutic approaches for combating alcohol abuse and alcoholism.
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