Stress Regulation of 5HT Receptors and the HPA Axis

描述：(申请人提供)这项建议的目的是研究 5-羟色胺(5-羟色胺)系统特异性分子的调节和相互作用 和边缘-下丘脑-垂体-肾上腺(LHPA)轴在大脑的关键区域 大鼠脑(海马体、下丘脑和前额叶皮质)；使用生化 和神经解剖学工具。5-羟色胺系统功能障碍与血管紧张素转换酶激活过度 LHPA轴是抑郁症中复制最多的两个生物学基础。 我们的总体假设是，这两个系统的变化是密切相关的 已链接。具体地说，根据我们之前的动物和人类尸检 研究中，我们提出了以下假设：1)糖皮质激素发挥作用 在5-羟色胺和皮质类固醇受体失调中的中心作用 抑郁和慢性压力；2)抗抑郁剂未能 防止LHPA过度活动与未能逆转这些相关 受体改变；3)阻断脑内糖皮质激素的作用 防止受体异常；以及4)早期的环境因素 生活可能导致LHPA‘功能障碍’和5-羟色胺受体异常。至 回答这些假设，在目标1和目标2上，我们将使用老鼠来研究 慢性应激是否会导致脑部5-羟色胺、皮质类固醇、 和CRH受体。我们还将调查抗抑郁药物是否能预防 这些变化，以及循环中的皮质类固醇是否在 这些由压力引起的受体“异常”。AIM 3将调查 服用脱氢表雄酮，一种具有抗糖皮质激素特性的雄激素，或 使用CR11受体拮抗剂将逆转和/或阻止这些 受体发生变化。目的4将调查大鼠的母体剥夺 使大脑在成年时更容易受到这些受体变化的影响。我们会 应用原位杂交、放射免疫细胞化学和受体 放射自显影定量：5HT1a和5HT2a受体，5HT转运体， 糖皮质激素和矿物皮质激素受体、促肾上腺皮质激素释放激素 (CRH)、CRH受体和CRH结合蛋白。这项建议把 分子/神经解剖学工具，以增加我们对 压力和抑郁。希望这一系列的“临床前”动物 研究将有助于增加我们对病理生理学的了解。 慢性应激的后果，将有助于阐明升高的作用 皮质类固醇在抑郁症中的作用，并将给我们一些关于如何治疗的提示， 或预防，脑内高皮质醇血症的累积效应。

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.