Molecular Basis for Sex-Selective Effects of Ethanol

描述(由申请人提供)：这项提案是第二次提交竞争性更新，以继续我们对酒精依赖和戒断的性别差异的神经生物学基础的研究。到目前为止，我们已经发现在酒精依赖和早期戒断过程中，雄性和雌性大鼠在几个大脑部位对GABA-A和NMDA受体的适应存在重要差异。我们最近发现，在酒精戒断后恢复的时间上，存在显著且强烈的行为性别差异。虽然男性和女性在24小时都显示出显著的戒断迹象，但女性在3天后似乎已经恢复，但男性没有。因此，这个项目的总体目标是阐明24小时和3天酒精戒断行为表达的机制基础。我们假设，酒精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性变化，这是由于男性和女性之间不同的荷尔蒙环境造成的。为了验证这一假设，我们将比较和对比年轻成年雄性、周期发情间期雌性和去卵巢雌性大鼠的研究结果。拟议的研究将使我们能够描述荷尔蒙调节在酒精戒断恢复过程中性别差异的重要性。本项目将通过以下目的来验证这一假说：1.评估几种酒精戒断行为，包括戒酒早期(24小时)和戒酒后(3天)对药物的反应；2.通过分析在这些相同的戒酒时间对GABA-A和NMDA受体的调节来识别伴随而来的大脑激活的性别差异；以及3.分析酒精戒断引起的GABA、谷氨酸和类固醇水平的变化。我们期望发现男性和骑自行车的女性之间不同的荷尔蒙环境调节GABA能和谷氨酸能神经传递的适应，从而使人从酒精戒断中恢复过来。这些拟议研究的结果应该表明，荷尔蒙状态导致的固有神经生物学调节是影响乙醇作用的重要因素，恢复适应不同于依赖的发展。增加我们对戒酒背后的性别选择机制的理解，应该有助于指导我们改进女性和男性戒酒的治疗方法。

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.