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

描述（由申请人提供）：酒精导致健康问题的主要方式之一是通过其对下丘脑-垂体-肾上腺（HPA）或“压力”轴的作用。有趣的是，男性和女性的HPA轴对压力和酒精等药物的反应不同。这项研究提出的一般假设是，性腺激素，如雌激素和睾酮改变神经元对酒精的反应，导致性二态性HPA轴功能。长期的工作目标是阐明解剖和功能神经机制的性别特异性HPA对酒精的反应在大鼠。如果要创造针对酒精使用和滥用引起的医学问题的性别特异性治疗方法，增加我们对性二态性HPA反应机制的理解是必要的。为了突出CNS在酒精激活HPA中的作用，所提出的实验将使用CNS上的相关性。该模型通过避免药物的有害外周作用（反馈至大脑并以非特异性方式改变其功能），简化了对HPA对酒精反应中严格脑介导的性别差异的研究。这种反馈极大地增加了HPA的活性，并极大地复杂化HPA对酒精反应的性别差异的研究。特定目标研究1将研究HPA相关神经元对酒精给药反应的性别差异的潜在机制。这项工作将首先集中在确定特定的大脑区域响应酒精，参与调节HPA轴，并敏感的性腺激素。然后，我们将探讨特定的性腺激素及其受体在调节HPA功能相关的神经元激活的功能作用。针对特定目标的研究2将研究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。该项目的目的是研究对酒精产生潜在有害的、性别特异性反应的基本中枢神经系统机制。 然后，可以利用这种形成来开发与性有关的治疗方法，以治疗与酒精有关的健康问题。公共卫生相关性：饮酒对男性和女性的健康都有不利影响。有趣的是，D

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Alcohol use causes detrimental health effects in both men and women. Interestingly, the d