This proposal is directed at determining the molecular mechanisms by which tolerance develops to anxiolytic actions of ethanol. The understanding of the mechanisms of tolerance development will provide information that should assist in the understanding of the motivation driving increased ingestion of alcohol. Our research design will utilize genetically-modified animals which carry a modification in an enzyme in their brains through which alcohol can exert its action (i.e., adenylyl cyclase). The transgenic mice and their """"""""wild-type"""""""" littermates will be treated acutely and chronically with ethanol. We will study the effect of drug administration on the animals' levels of anxiety and changes in drug response over a period of chronic drug administration. We will also monitor environmental influences on drug response after chronic ethanol treatment. Simultaneously, we will monitor the function and changes in function of intraneuronal signalling systems that control gene transcription. Finally, we will use gene- expression arrays to monitor which genes are modulated in the short- term and long-term by ethanol administration and which genes are related to tolerance development. In all, our studies should provide an excellent foundation for understanding the neuroadaptive processes leading to ethanol tolerance in reference to the anxiolytic action of this drug.
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