Stress Regulation of 5HT Receptors and the HPA Axis

5HT 受体和 HPA 轴的应激调节

• 批准号: 6879720
• 负责人: Juan F Lopez
• 金额: $ 30.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6879720
• 关键词: antidepressants; autoradiography; behavioral /social science research tag; binding proteins; corticosteroids; corticotropin releasing factor; dehydroepiandrosterone; depression; glucocorticoids; hormone receptor; hypothalamic pituitary adrenal axis; hypothalamus; immunocytochemistry; in situ hybridization; laboratory rat; limbic system; pathologic process; polymerase chain reaction; prefrontal lobe /cortex; psychological stressor; receptor expression; serotonin receptor; western blottings

DESCRIPTION: (provided by applicant) The goal of this proposal is to study the regulation and interaction of specific molecules of the Serotonrn (5HT) system and the Limbic-Hypothalamic-Pituitary-Adrenal (LHPA) axis in key regions of the rat brain (hippocampus, hypothalamus, and prefrontal cortex); using biochemical and neuroanatomical tools. Dysfunction of the 5HT system and overactivity of the LHPA axis are two of the most replicated biological fmdings in depression. Our overall hypothesis is that the alterations in these two systems are closely linked. Specifically, based on our previous animal and human postmortem studies, we propose the following hypotheses: 1) that glucocorticoids play a central role in the 5HT and corticosteroid receptor dysregulation found in depression and in chronic stress; 2) that failure of an antidepressant to prevent the LHPA overactivity is associated with a failure to reverse these receptor changes; 3) that blocking the effect of glucocorticoids in brain will prevent the receptor abnormalities; and 4) that environmental factors early in life can contribute to LHPA 'dysfunction' and 5HT receptor abnormalities. To answer these hypotheses, on Aims 1 and 2 we will use rats to investigate whether chronic stress causes concomitant changes in brain 5HT, corticosteroid, and CRH receptors. We will also investigate whether antidepressants prevent these changes, and whether circulating corticosteroids have a central role on these stress-induced receptor 'abnormalities'. Aim 3 will investigate whether administration of DHEA, an androgen with antiglucocorticoid properties, or administration of a CR11 receptor antagonist, will reverse and/or prevent these receptor changes. Aim 4 will investigate whether maternal deprivation in rats makes the brain more vulnerable to these receptor changes in adulthood.We will use in situ hybridization, radioimmunocytochemistry, and receptor autoradiography to quantify: 5HT1a and 5HT2a receptors, 5HT transporter, Glucocorticoid and Mineralocorticoid receptors, Corticotropin releasing hormone (CRH), CRH receptors, and CRH binding protein. This proposal brings together molecular/neuroanatomical tools, to increase our knowledge of the link between stress and depression. It is hoped that these series of 'preclinical' animal studies will help increase our understanding of the pathophysiological consequences of chronic stress, will help clarify the role of elevated corticosteroids in depression, and will give us someclues about how to treat, or prevent, the cumulative effect of hypercortisolemia in brain.

描述：（由申请人提供）本提案的目标是研究 血清素 (5HT) 系统特定分子的调节和相互作用 以及大脑关键区域的边缘-下丘脑-垂体-肾上腺 (LHPA) 轴 大鼠大脑（海马体、下丘脑和前额皮质）；使用生化 和神经解剖学工具。 5HT系统功能障碍和过度活跃 LHPA 轴是抑郁症中最常见的两个生物学发现。 我们的总体假设是这两个系统的变化密切相关 已链接。具体来说，根据我们之前的动物和人类尸检 研究中，我们提出以下假设：1）糖皮质激素发挥作用 5HT 和皮质类固醇受体失调中的核心作用 抑郁症和慢性压力； 2）抗抑郁药失败 防止 LHPA 过度活动与逆转这些失败有关 受体变化； 3）阻断糖皮质激素在大脑中的作用会 防止受体异常； 4）早期的环境因素 生活可能导致 LHPA“功能障碍”和 5HT 受体异常。到 回答这些假设，对于目标 1 和 2，我们将使用老鼠进行研究 慢性压力是否会导致大脑 5HT、皮质类固醇、 和CRH受体。我们还将调查抗抑郁药是否可以预防 这些变化，以及循环皮质类固醇是否具有核心作用 这些压力引起的受体“异常”。目标 3 将调查是否 给予 DHEA（一种具有抗糖皮质激素特性的雄激素），或 给予 CR11 受体拮抗剂，将逆转和/或预防这些 受体变化。目标 4 将调查大鼠是否遭受母性剥夺 使大脑在成年后更容易受到这些受体变化的影响。我们将 使用原位杂交、放射免疫细胞化学和受体 放射自显影定量：5HT1a 和 5HT2a 受体、5HT 转运蛋白、 糖皮质激素和盐皮质激素受体、促肾上腺皮质激素释放激素 (CRH)、CRH 受体和 CRH 结合蛋白。该提案汇聚了 分子/神经解剖学工具，以增加我们对两者之间联系的了解 压力和抑郁。希望这一系列“临床前”动物 研究将有助于加深我们对病理生理学的了解 慢性压力的后果，将有助于阐明升高的作用 皮质类固醇治疗抑郁症，并将为我们提供一些如何治疗的线索， 或预防大脑中高皮质醇血症的累积效应。