The objective of this proposal for a Scientist Development Award is for the candidate to retrain in the field of alcohol research utilizing molecular genetic approaches to investigate the potential role of gender and endogenous steroid modulation of GABAA receptors in the development and manifestation of ethanol dependence. Increasing evidence suggests that alterations in GABAergic neurotransmission underlie some of the pathophysiological effects of ethanol. The purpose of the present proposal is to examine the influence of gender on regulation of GABAA receptor gene expression in ethanol-dependent rats. Gonadal hormones have been shown to produce an altered profile of GABAergic regulation in female rats compared to their male counterparts. Gender differences in seizure susceptibility, anxiety and sedation have been observed. The first goal will be to ascertain whether gender influences ethanol-induced alterations in seizure susceptibility. Prior investigations have shown that female rats have decreased seizure sensitivity compared to male rats, as well as variations in seizure sensitivity across estrous (rat) and the menstrual cycle (human). The proposed studies will determine whether female gender effects the proconvulsant activity of chronic ethanol consumption. The second goal of this proposal will be to determine if ethanol-dependence produces different effects on GABAA receptor subunit mRNA levels in female as compared to male rats. Our lab has shown that ethanol selectively alters several GABAA receptor alpha subunit mRNA levels in the male rat cortex and cerebellum. The proposed studies will show whether the effects of ethanol on GABAA receptor subunit expression are gender-specific. The final goal will be to determine whether the endogenous neurosteroid, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha-THP) influences alterations seen in GABAA receptor subunit composition following chronic ethanol exposure. A major metabolite of progesterone, 3alpha-THP binds stereoselectively and with high affinity to GABAA receptors and is the most potent endogenous GABAergic ligand known. Taken together, these experiments will test the hypothesis that gender influences ethanol- induced alterations in GABAA receptor gene expression related to the acquisition and maintenance of ethanol dependence. Investigation of the role of endogenous neuroactive steroids in imparting these effects may afford insight into mechanisms which underlie or protect against the pathophysiological effects of ethanol. These findings should have important implications for the treatment of alcoholism in males as well as females.
