Molecular Basis for Sex-Selective Effects of Ethanol

描述（由申请人提供）：本提案是第二次提交竞争性更新，以继续我们对乙醇依赖和戒断中性别差异的神经生物学基础的研究。迄今为止，我们已经确定了雄性和雌性大鼠在乙醇依赖和早期戒断过程中对GABA-A和NMDA受体的适应在几个大脑部位的重要差异。我们最近发现，在酒精戒断后恢复的时间上，行为上存在显著的性别差异。而雄性和雌性在24小时时都表现出明显的戒断迹象，雌性在3天后恢复，而雄性没有。因此，本项目的总体目标是阐明24小时和3天乙醇戒断行为表达的机制基础。我们假设乙醇戒断后恢复的差异涉及gaba能和谷氨酸能神经传递的性别选择变化，这是由于男性和女性之间不同的激素环境造成的。为了验证这一假设，我们将比较和对比年轻成年雄鼠、绝经期雌鼠和去卵巢雌鼠的研究结果。拟议的研究将使我们能够描述激素调节在乙醇戒断后恢复中赋予性别差异的重要性。本项目将通过以下几个目标来检验这一假设：评估几种乙醇戒断行为，包括对药物治疗的反应，在早期（24小时）和后期（3天）戒断，2。2 .通过分析GABA-A和NMDA受体在同一戒断时间的调节来鉴定脑激活的伴随性差异；分析乙醇戒断诱导的GABA、谷氨酸和类固醇水平的变化。我们期望发现，雄性和循环中的雌性之间不同的激素环境调节gaba能和谷氨酸能神经传递的适应性，从而从乙醇戒断中恢复过来。这些拟议的研究结果表明，激素状态引起的内在神经生物学调节是影响乙醇作用的重要因素，其适应性不同于恢复和依赖的发展。增加我们对戒酒背后的性别选择机制的理解，将有助于指导我们改进对女性和男性戒酒的治疗。

DESCRIPTION (provided by applicant): This proposal is the second submission of a competing renewal to continue our investigations into the neurobiological basis for sex differences in ethanol dependence and withdrawal. To date, we have identified important differences between male and female rats in adaptations of GABA-A and NMDA receptors during ethanol dependence and early withdrawal across several brain sites. We recently found significant and robust behavioral sex differences in the timing for recovery from ethanol withdrawal. Whereas both males and females showed significant withdrawal signs at 24 hr, females, but not males, appeared to have recovered by 3 days. Therefore, the overall goal of this project is to elucidate the mechanistic underpinnings for behavioral expressions of ethanol withdrawal at 24 hr and 3 days. We hypothesize that differences in recovery from ethanol withdrawal involve sex-selective changes in GABAergic and glutamatergic neurotransmission that occur as a result of the differing hormonal milieu between males and females. To test this hypothesis we will compare and contrast findings in young adult male, cycling diestrus female and ovariectomized female rats. The proposed studies will allow us to delineate the importance of hormonal modulation in conferring sex differences in recovery from ethanol withdrawal. This project will test the hypothesis by these aims: 1. assessment of several ethanol withdrawal behaviors, including responses to drug treatments, at early (24 hr) and later (3 days) withdrawal, 2. identification of concomitant sex differences in brain activation with analysis of modulation of GABA-A and NMDA receptors at these same times of withdrawal, and 3. analysis of ethanol withdrawal-induced changes in GABA, glutamate and steroid levels. We expect to find that the differing hormonal milieu between males and cycling females regulates adaptations of GABAergic and glutamatergic neurotransmission that confers recovery from ethanol withdrawal. Findings resulting from these proposed studies should show that inherent, neurobiological regulation due to hormonal status is an important factor influencing actions of ethanol, with adaptations being different for recovery than development of dependence. Increasing our understanding of sex-selective mechanism underlying withdrawal should help guide us towards improving treatments for alcohol withdrawal in both women and men.