PSYCHOBIOLOGY OF CORTICOTROPIN-RELEASING FACTOR

描述：（改编自申请人摘要）本申请是 NIH MH-42088的竞争性更新申请，寻求五年的支持， 这将代表15-19年这个项目的心理生物学， 促肾上腺皮质激素释放因子（CRF）。在过去的几年里，这笔赠款 提供了大量证据，证明含CRF的神经元在 调解的反应，特点相当详细， CRF在哺乳动物CNS中的神经传递作用，也许大多数 重要的是，有助于迅速发展的dah基地，支持 抑郁症患者CRF分泌过多的假说。的确， 来自本实验室和其他实验室的贡献， 多学科方法提供了明确的证据， 抑郁症患者脑内CRF阳性神经元异常， 特别是那些患有严重抑郁症的患者。目前的提案寻求 为了在很大程度上根据在研究期间获得的发现来扩展这项工作， 目前的资助期（第一和第二阶段的目标也是新的方向（遗传学 目标3和4）。具体来说，调查人员希望继续验尸 脑组织研究，以进一步表征含CRF的 神经元和含CRF受体的神经元通过仔细检查CRF和CRF 受体mRNA表达，以及关注CRF 2受体和 尿皮质素小分子非肽类CRF 1受体的研究进展 拮抗剂的出现在一定程度上是由于研究人员在以下方面的进展： 该领域随着其可用性的增加，行为，内分泌， 这些CRF 1受体的神经化学反应 将表征拮抗剂。此外，对中止的反应 将对这些化合物进行评估。在一个新的抑郁症动物模型中， 基于强迫游泳试验中的敏感性应激， 所有类别的抗抑郁药，研究人员将确定是否 CRF 1受体拮抗剂具有抗抑郁作用。此外， 该动物中存在的CNS CRF神经元系统和受体的改变 模特？因为有证据表明，CRF功能的改变似乎是 至少部分地负责焦虑和/或抑郁表型， 在一些动物模型中，研究人员将绘制数量性状基因座， (QTL)控制CRF系统的表达。这些研究将提供 新的信息CRF nepronal系统的作用，在病理生理学的 抑郁症，在系统性CRF 1受体拮抗剂的动物模型中 局

DESCRIPTION: (Adapted from applicant's abstract) This application is the competitive renewal application of NIH MH-42088, seeking five years of support, which would represent years 15-19 of this project on the Psychobiology of Corticotropin-Releasing Factor (CRF). In the past years, this grant has provided much evidence for a preeminent role for CRF-containing neurons in mediating the response, characterized in considerable detail the neurotransrnitter role of CRF in the mammalian CNS, and perhaps most importantly, contributed to the burgeoning dah base which supports the hypothesis that CRF is hypersecreted in patients with major depression. Indeed, contributions from this and other laboratories using a variety of multidisciplinary approaches have provided unequivocal evidence for hyperactivity of CRF-containing in neurons patients with major depression, particularly those patients with severe depression. The current proposal seeks to extend this work in directions largely based upon findings obtained during the current funding period (aims I & 2 in a new direction as well (genetics aims 3 & 4). Specifically, the investigators wish to continue the postmortem brain tissue studies to further characterize that alterations in CRF-containing neurons and CRF receptor-containing neurons by scrutinizing CRF and CRF receptor mRNA expression, as well as focusing on the CRF2 receptor and urocortin The development of small molecule, non-peptide CRF1 receptor antagonists has occurred to some extent due to the investigators progress in this field. With their increasing availability, the behavioral, endocrine, and neurochemical responses chronic administration of these CRF1 receptor antagonists will be characterized. Moreover, the responses to discontinuation of these compounds will be assessed. In a novel animal model of depression based upon sensitivity stress in the forced-swim test that is highly sensitive to all classes of antidepressants, the investigators will determine whether CRF1 receptor antagonists exhibit an antidepressant profile. Moreover, are alterations in CNS CRF neuronal systems and receptors present in this animal model? Because evidence suggests that altered CRF function appears to be responsible, at least in part, for the anxiety and/or depression phenotype in some animal models, the investigators will map the quantitative trait loci (QTL) that control the expression of the CRF system. These studies will provide novel information on the role of CRF nepronal systems in the pathophysiology of depression, in animal models of systemic CRF1 receptor antagonist administration.