GENDER SPECIFIC EFFECTS OF ETHANOL ON GABA A RECEPTORS

科学家发展奖的目的是为了 在酒精研究领域进行再培训的候选人， 用分子遗传学方法研究性别的潜在作用 和GABAA受体的内源性类固醇调节 和酒精依赖的表现。 越来越多的证据表明 γ-氨基丁酸能神经传递的改变是一些 乙醇的病理生理效应。本提案的目的 研究性别对GABAA受体基因调控的影响， 在乙醇依赖大鼠中的表达。性腺激素已经被证明 在雌性大鼠中产生改变的GABA能调节谱， 他们的男性同行。 癫痫易感性的性别差异， 已经观察到焦虑和镇静。 第一个目标是 确定性别是否影响乙醇诱导的癫痫发作改变 易感性 先前的研究表明，雌性大鼠 与雄性大鼠相比，癫痫敏感性降低， 在整个发情期（大鼠）和月经周期的癫痫敏感性 （人类）。拟议的研究将确定女性性别是否影响 慢性酒精摄入的致惊厥活性。 第二 这项提案的目标是确定乙醇依赖是否会产生 对雌性大鼠GABAA受体亚单位mRNA水平的影响 与雄性大鼠相比。 我们的实验室已经证明乙醇选择性地改变 雄性大鼠皮质中几种GABAA受体α亚单位mRNA水平 和小脑拟议的研究将表明， 乙醇对GABAA受体亚基表达的影响具有性别特异性。的 最终的目标是确定内源性神经类固醇， 3 α-羟基-5 α-葡聚糖-20-酮（3 α-THP）影响改变 在慢性乙醇后GABAA受体亚基组成中观察到 exposure.孕酮的主要代谢物，3 α-THP结合 具有立体选择性和对GABAA受体的高亲和力，是 已知最有效的内源性GABA能配体。 综上所述各项 实验将检验性别影响乙醇的假设， 诱导GABAA受体基因表达的改变， 获取和维持对乙醇的依赖。 调查 内源性神经活性类固醇在产生这些作用中的作用可能 提供深入了解的机制，其基础或保护免受 乙醇的病理生理效应。 这些发现应该 对男性酗酒治疗的重要意义， 女性

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.