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

性腺激素在大鼠饮酒后 HPA 反应中的作用

• 批准号: 7803671
• 负责人: DANIEL SELVAGE
• 金额: $ 3.81万
• 依托单位: IDAHO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2010-08-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7803671
• 关键词: Adrenal Glands; Adrenal hormone preparation; Alcohol abuse; Alcohol consumption; Alcohols; Animals; Area; Back; Blood Circulation; Brain; Brain region; Castration; Cells; Chemicals; Diffuse; Drug effect disorder; Endocrine; Estrogens; Estrous Cycle; Estrus; FOS gene; Feedback; Female; Fertility; Gender; Generations; Genetic Transcription; Glean; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Grant; Health; Hormonal; Hormone Receptor; Hormones; Hypothalamic structure; Immediate-Early Genes; In Situ Hybridization; Investigation; Laboratories; Lead; Link; Measurable; Mechanics; Mediating; Medical; Methods; Modeling; Modification; Nature; Neuraxis; Neurons; Neurotransmitter Receptor; Neurotransmitters; Ovariectomy; Peripheral; Pharmaceutical Preparations; Phenotype; Pituitary Gland; Pituitary-Adrenal System; Play; Population; Progesterone; Protein Isoforms; Rattus; Regulation; Relative (related person); Research; Role; Safe Sex; Sex Characteristics; Sexual Development; Site; Staging; Stimulus; Stress; System; Techniques; Testing; Testosterone; Ventricular; Woman; Work; addiction; alcohol abuse therapy; alcohol and other drug; alcohol effect; alcohol related problem; alcohol response; biological adaptation to stress; design; drug of abuse; drug withdrawal; feeding; hydrophilicity; immunocytochemistry; lateral ventricle; male; men; novel; psychologic; receptor; research study; response; sex; stressor

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 longterm 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 relatively novel alcohol delivery method of microinfusing a modest amount of the drug directly into the cerebroventricular systems (icv administration) of rats. Alcohol administered in this manner does not cause neuronal damage and does not leak to the periphery in measurable amounts, but has highly explicit actions 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 secretion of stresslinked hormones following icv alcohol administration. Overall, this research will elucidate the neuroanatomical loci and hormone receptor machinery responsible for sex- specific HPA responses to alcohol. This information can then be used to develop sex- related treatments for alcohol- related health problems.

酒精引起健康问题的主要方式之一是通过其对人体的作用， 下丘脑-垂体-肾上腺（HPA）或“应激”轴。有趣的是，男性和女性的HPA轴 女性对压力和酒精等药物的反应不同。一般假设 这项拨款中提出的研究是，性腺激素，如雌激素和睾丸激素， 神经元对酒精的反应性，导致HPA轴功能的性二态性。的长期 目的是阐明神经元的解剖和功能机制 潜在的性别特异性HPA对酒精的反应。提高我们对 如果性别特异性， 将制定针对饮酒和滥用引起的医疗问题的治疗方法。为了 为了突出中枢神经系统在酒精激活HPA中的作用，所提出的实验将使用 直接微量注入适量药物的相对新颖的酒精输送方法 进入大鼠的脑室系统（ICV给药）。酒精在这个 这种方式不会引起神经元损伤，并且不会以可测量的方式泄漏到外周。 量，但对CNS具有高度明确的作用。该模型简化了对严格 通过消除有害的外周神经， 药物的作用反馈到大脑并以非特异性方式改变其功能。等 反馈极大地增加了HPA的活性，并极大地使性研究复杂化 HPA对酒精反应的差异。具体目标研究1将调查 HPA相关神经元对酒精反应的性别差异机制 局这项工作将首先集中在识别对酒精敏感的特定大脑区域， 参与HPA轴的调节，对性腺激素敏感。然后我们将调查 特异性性腺激素及其受体在调节神经元功能中的作用 与HPA功能相关的激活。针对特定目标的研究2将通过以下方式研究其机制： 其中性腺类固醇和它们的受体相互作用，导致与压力相关的性依赖性分泌 icv酒精给药后的激素。总的来说，这项研究将阐明 神经解剖学位点和激素受体机制负责性别特异性HPA 对酒精的反应。这些信息可以用于开发与性有关的治疗方法， 与酒精有关的健康问题