Several lines of evidence have suggested that GABAA receptor activity may be involved, at least in part, in the pharmacologic and behavioral actions of ethanol. The purpose of the present proposal is to examine the role of ethanol in modulating the expression of GABAA receptor subunits in the rat brain. Measurement of GABAA receptor mRNA levels is the most sensitive method for detecting alterations in the expression of receptor subunits. The first goal is to ascertain if acute or chronic ethanol administration alters the level of GABAA receptor subunit mRNAs in the cerebral cortex. Preliminary evidence suggests that alpha1 subunit mRNA levels are modulated by acute as well as chronic ethanol exposure. Prolonged ethanol inhalation selectively reduces the levels of GABAA receptor alpha1 and alpha2, but not alpha3 subunit mRNAs in the rat cerebral cortex. This is a specific effect of ethanol since there is no change in the levels of total RNA, ribosomal RNA, polyadenylated RNA or mRNA levels for glutamate decarboxylase or beta- actin. The next goal is to study the effects of acute and chronic ethanol administration on GABAA receptor mRNAs in various brain regions where the composition of GABAA receptor subunits differ from the cerebral cortex. If ethanol administration has differential effects on the various GABAA isoreceptors, there may be regional differences in the effect of ethanol on GABAA receptor subunit mRNA levels. The third goal is to determine whether the effects of ethanol on GABAA receptor alpha subunit mRNA levels are mediated by the receptor. These studies will test whether the effect of ethanol in rat cerebral cortex is dose-dependent and reversible by a GABA receptor antagonist, bicuculline or the benzodiazepine receptor inverse agonist and ethanol antagonist, Ro15-4513. Further, we will investigate whether alterations in intracellular Ca++ or cAMP are involved in the rapid reduction in mRNA levels. The final goal of these studies is to determine whether genetic differences in ethanol withdrawal seizure sensitivity are correlated with an alteration in a) the expression of GABAA receptor subunit mRNAs or b) the effect of ethanol on the levels of GABAA receptor subunit mRNAs. These experiments will test the hypothesis that the structure or the regulation of the GABAA receptor is different in ethanol withdrawal seizure prone and withdrawal seizure resistant rats. These studies will provide the foundation for a systematic investigation of the genetic basis for differences in behavioral sensitivity and preference for ethanol at the level of gene regulation. The results of these studies should have important implications for our understanding of the neurobiology of ethanol tolerance and withdrawal and may lead to an understanding of the causes of alcoholism.
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