MOLECULAR BASIS FOR GENDER SELECTIVE EFFECTS OF ETHANOL

该提案的目标是描述乙醇依赖背后性别差异的分子基础。 目的是检验性别影响慢性乙醇暴露引起的 GABA 和谷氨酸能系统神经适应的假设。 GABAA 和 NMDA 受体是大脑中介导乙醇作用的关键位点。 乙醇依赖性导致 GABAA 和 NMDA 受体基因表达和功能的亚基选择性改变。 我们最近发现，长期乙醇消耗对 GABAA 受体 α 和 NMDA NR1 亚基表达的影响存在显着的性别差异。 这表明性别影响乙醇依赖对这两个关键神经递质系统基因表达的影响。 这表明与乙醇依赖和戒断相关的神经适应可能取决于乙醇暴露的激素背景。然而，几乎没有证据表明乙醇依赖和戒断行为与观察到的 GABAA 和 NMDA 受体分子变化之间存在直接关联。 拟议的研究将通过将乙醇依赖的发展和恢复与基因表达和受体调节的变化联系起来，探讨乙醇依赖和戒断影响中性别差异的分子基础。 该提案将检验以下假设：乙醇依赖会导致 1) GABAA 受体调节、功能和基因表达，2) NMDA 受体调节、功能和基因表达，以及 3) 几种关键神经活性类固醇水平的性别选择性改变。 我们将确定这些改变是否与乙醇依赖和戒断的行为表现存在时间相关性。 这些研究尤其重要，因为对长期乙醇消耗的神经适应的表达因性别而异，即使两种性别都表现出相似的依赖和戒断行为迹象。 确定 GABAA 或 NMDA 受体功能或分子变化的时间是否与依赖性和戒断的生理表现（包括不同内源性调节的影响）相关是至关重要的。 这些研究对于了解男性和女性乙醇依赖和戒断的神经生物学基础非常重要。

The goal of this proposal is to characterize the molecular basis for gender differences underlying ethanol dependence. The objective is to test the hypothesis that gender influences neuroadaptations of GABA and glutamatergic systems elicited by chronic ethanol exposure. GABAA and NMDA receptors are key sites in the brain mediating the effects of ethanol. Ethanol dependence results in subunit selective alterations in gene expression and function for both GABAA and NMDA receptors. We have recently found profound gender differences in the effects of chronic ethanol consumption on GABAA receptor alpha and NMDA NR1 subunit expression. This shows that gender impacts the effects of ethanol dependence on gene expression for these two key neurotransmitter systems. This suggests that neuroadaptations associated with ethanol dependence and withdrawal may be dependent on the hormonal context of the ethanol exposure. However, there is little evidence showing a direct association between ethanol dependence and withdrawal behaviors and the molecular changes observed for GABAA and NMDA receptors. The proposed studies will investigate the molecular basis for gender differences in the effects of ethanol dependence and withdrawal by correlating the development of and recovery from ethanol dependence with changes in gene expression and receptor regulation. This proposal will test the hypothesis that ethanol dependence induces gender-selective alterations in 1) GABAA receptor regulation, function and gene expression, 2) NMDA receptor regulation, function and gene expression, and 3) levels of several key neuroactive steroids. We will determine whether these alterations show a temporal correlation with behavioral manifestations of ethanol dependence and withdrawal. These studies are particularly important as the expression of neuroadaptations to chronic ethanol consumption varies according to gender, even though both genders display similar behavioral signs of dependence and withdrawal. It is critical to ascertain whether the timing of functional or molecular changes in GABAA or NMDA receptors are associated with physiological manifestations of dependence and withdrawal, including the influence of differing endogenous regulation. These investigations are important for understanding the neurobiological basis of ethanol dependence and withdrawal in both males and females.