Stress Regulation of 5HT Receptors and the HPA Axis

描述：（由申请人提供）本提案的目标是研究 5-羟色胺（5-HT）系统特定分子的调节和相互作用 和边缘-下丘脑-垂体-肾上腺（LHPA）轴的关键区域， 大鼠大脑（海马体、下丘脑和前额皮质）;使用生物化学 和神经解剖学工具。5-HT系统功能障碍和 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，这两个系统中的改变是密切相关的。 有联系特别是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， 在5 HT和皮质类固醇受体失调中的中心作用， 抑郁症和慢性压力; 2）抗抑郁药失败， 防止LHPA过度活动与未能逆转这些 受体的变化; 3）阻断糖皮质激素在脑内的作用， 防止受体异常; 4）环境因素在早期 生活可以导致LHPA“功能障碍”和5 HT受体异常。到 为了回答这些假设，在目标1和2中，我们将使用大鼠进行研究。 慢性应激是否引起脑5-HT，皮质类固醇， CRH受体。我们还将调查抗抑郁药是否能预防 这些变化，以及循环皮质类固醇是否在 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 施用CR 11受体拮抗剂将逆转和/或预防这些变化。 受体变化目的4：探讨大鼠母体剥夺是否 使大脑在成年后更容易受到这些受体变化的影响。 应用原位杂交、放射免疫细胞化学和受体 放射自显影定量：5 HT 1a和5 HT 2a受体，5 HT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。该提案汇集了 分子/神经解剖学工具，以增加我们对 压力和抑郁希望这些系列的“临床前”动物 研究将有助于增加我们对病理生理学的理解， 慢性压力的后果，将有助于澄清升高的作用， 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线索， 或预防大脑皮质醇过多的累积效应。

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.