GENDER SPECIFIC EFFECTS OF ETHANOL ON GABA A RECEPTORS

这项科学家发展奖提案的目的是 在酒精研究领域接受再培训的候选人利用 用分子遗传学方法研究性别的潜在作用 GABAA受体在发育中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 GABA能神经传递的改变是一些 乙醇的病理生理效应。本提案的目的是 研究性别对GABAA受体基因调控的影响 在酒精依赖大鼠中的表达。性腺激素已经被证明可以 在雌性大鼠身上产生改变的GABA能调节的比较 给他们的男性同龄人。癫痫易感性的性别差异， 观察到焦虑和镇静。第一个目标将是 确定性别是否影响酒精引起的癫痫发作改变 敏感度。先前的调查表明，雌性老鼠有 与雄性大鼠相比，癫痫敏感度降低，以及变异 发情(大鼠)和月经周期的癫痫敏感度 (人类)。拟议中的研究将确定女性的性别影响 慢性酒精摄入的促惊厥作用。第二 这项提案的目标将是确定乙醇依赖是否会产生 不同因素对女性AS患者GABAA受体亚单位基因表达的影响 与雄鼠相比。我们的实验室已经证明，乙醇可以选择性地改变 雄性大鼠大脑皮质几种GABAA受体α亚单位的mRNA水平 还有小脑。拟议的研究将表明， 乙醇对GABAA受体亚单位表达的影响具有性别特异性。这个 最终目标将是确定内源性神经类固醇是否， 3α-羟基-5α-孕烷-20-酮(3α-THP)影响改变 慢性酒精中毒后的GABAA受体亚单位组成 曝光。孕酮的主要代谢物3α-THP结合 对GABAA受体具有立体选择性和高亲和力，是 已知的最有效的内源性GABA能配体。这些加在一起， 实验将检验性别影响酒精的假设-- GABAA受体相关基因表达的诱导改变 获得并维持对酒精的依赖。对这一事件的调查 内源性神经活性类固醇在传递这些效应中的作用可能 洞察支撑或保护不受 乙醇的病理生理效应。这些发现应该是 对男性酒精中毒治疗的重要意义以及 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.