Role of gonadal hormones in HPA responses to alcohol administration in the rat

酒精引起健康问题的主要途径之一是它对下丘脑-垂体-肾上腺（HPA）或“压力”轴的作用。有趣的是，男性和女性的下丘脑轴对压力源和酒精等药物的反应不同。这项研究的一般假设是，性激素，如雌激素和睾酮，改变了神经元对酒精的反应，导致性变态的下丘脑轴功能。这项工作的长期目标是阐明大鼠性别特异性HPA对酒精反应的解剖学和功能性神经机制。如果要为酒精使用和滥用引起的医疗问题创造针对性别的治疗方法，增加我们对两性二态HPA反应机制的理解是必要的。为了突出中枢神经系统在酒精活化HPA中的作用，本实验将利用中枢神经系统上的关系。该模型简化了HPA对酒精反应中严格由大脑介导的性别差异的研究，消除了药物反馈到大脑并以非特异性方式改变其功能的有害外周作用。这种反馈极大地增加了HPA的活性，使HPA对酒精反应的性别差异研究变得非常复杂。特异性目的1的研究将探讨HPA相关神经元对酒精反应的性别差异机制。这项工作将首先集中在确定对酒精有反应的特定大脑区域，参与调节下丘脑轴，并对性腺激素敏感。然后，我们将探讨特定性腺激素及其受体在调节与HPA功能相关的神经元激活中的功能作用。特异性目的2的研究将探讨性腺类固醇及其受体相互作用导致性别依赖性血清对两性有不同影响的机制。这项计划的目的是调查中枢神经系统的基本机制，这些机制对酒精的形成产生潜在的有害的、性别特异性的反应，然后可以用来开发与酒精相关的健康问题的性相关治疗。

One of the main ways that alcohol causes health problems is by its actions on the hypothalamus-pituitary-adrenal (HPA) or "stress" axis. Interestingly, the HPA axes of males and females respond differently to stressors and to drugs like alcohol. The general hypothesis for the research proposed in this grant is that gonadal hormones such as estrogen and testosterone alter neuronal responsiveness to alcohol, resulting in sexually dimorphic HPA axis function. The long- term objective of the work is to elucidate the anatomical and functional neuronal machinery underlying sex- specific HPA responses to alcohol in rats. Increasing our understanding of the mechanisms responsible for sexually dimorphic HPA responses is imperative if gender- specific treatments for medical problems that arise with alcohol use and abuse are to be created. In order to highlight the role of the CNS in HPA activation by alcohol, the proposed experiments will use the relatiactions on the CNS. This model simplifies the study of strictly brain- mediated sex differences in HPA responses to alcohol by obviating the noxious peripheral actions of the drug that feed back to the brain and alter its function in a non-specific manner. Such feedback dramatically increases HPA activity, and tremendously complicates the study of sex differences in HPA responses to alcohol. Studies for Specific Aim 1 will investigate the mechanisms underlying sex differences in HPA- linked neuronal responses to alcohol administration. This work will first focus on identifying specific brain regions responsive to alcohol, involved in the regulation of the HPA axis, and sensitive to gonadal hormones. We will then probe the functional roles of specific gonadal hormones and their receptors in regulating neuronal activation relevant to HPA function. Studies for Specific Aim 2 will investigate the mechanisms by which gonadal steroids and their receptors interact to cause sex- dependent serug has different effects on the two sexes. The purpos of the proposed project is to investigate the basic central nervous system mechanisms that generate potentially harmful, sex- specific responses to alcohol formation can then be used to develop sex- related treatments for alcohol- related health problems.