CORTICOTROPIN-RELEASING FACTOR-SEROTONIN INTERACTIONS

促肾上腺皮质激素释放因子-血清素相互作用

• 批准号: 6994444
• 负责人: RITA VALENTINO
• 金额: $ 53.1万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6994444
• 关键词: afferent nerve; autoradiography; brain mapping; corticotropin releasing factor; depression; dorsal raphe nucleus; electron microscopy; electrophysiology; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; laboratory rat; microdialysis; neurochemistry; neuropathology; neurotransmitter transport; prosencephalon; receptor binding; receptor expression; receptor sensitivity; serotonin; stress

DESCRIPTION (provided by applicant): Corticotropin-releasing factor (CRF) and the serotonergic (5-HT)-dorsal raphe nucleus (DRN) system have been independently implicated in the acute response to stress and in stress-related psychiatric disorders (e.g., anxiety, depression). During the last few years, we provided evidence that these two systems are anatomically and functionally linked in the response to stress. Thus, we demonstrated that CRF regulates DRN neuronal activity and 5-HT release in forebrain targets in response to acute stress. Moreover, we demonstrated that repeated stress results in cross-adaptation of the DRN-5-HT system to CRF and subsequent stress. The guiding hypothesis of this competing renewal is that CRF neuromodulation of the DRN-5-HT system underlies certain components of the behavioral limb of the acute stress response and that stress-induced plasticity in this function of CRF underlies psychiatric symptoms associated with repeated or chronic stress. The following AIMs integrate diverse approaches to test this hypothesis. AIM 1: will use in vivo microdialysis and electrophysiology to elucidate specific neuronal and neurochemical consequences of selectively activating CRF-R1 vs. CRF-R2 receptors within the DRN. AIM 2: will identify the anatomical substrates and circuitry by which CRF impacts on the DRN-5-HT system using immunohistochemistry, in situ hybridization and electron microscopy. AIM 3: will identify behavioral consequences of selectively activating CRF-R1 vs. CRF-R2 receptors within the DRN. AIM 4: will examine stress-induced adaptation of the DRN-5-HT system with regard to a) the role of CRF, b) the underlying mechanisms and c) whether neurochemical adaptation is causal to behavioral adaptation (using in vivo microdialysis, behavior and receptor autoradiography). Our previous work introduced the innovative idea that CRF-5-HT interactions are a pathophysiological focus of psychiatric disorders and a target of novel psychotherapeutic agents. The proposed studies will thoroughly characterize these interactions from a cellular to behavioral level. As such, they will enhance our understanding of the role of stress in psychopathology and indicate novel targets for the treatment of stress-related psychiatric disorders.

描述（由申请人提供）：促肾上腺皮质激素释放因子（CRF）和 血清素能（5-HT）-中缝背核（DRN）系统 独立地涉及对压力的急性反应以及与压力相关的 精神疾病（例如焦虑、抑郁）。在过去的几年里， 我们提供的证据表明这两个系统在解剖学和功能上都是 与对压力的反应有关。因此，我们证明了 CRF 调节 DRN 前脑目标响应急性反应的神经元活动和 5-HT 释放 压力。此外，我们证明重复的压力会导致 DRN-5-HT 系统对 CRF 和随后的应激的交叉适应。这 这种竞争性更新的指导性假设是 CRF 神经调节 DRN-5-HT 系统是动物行为肢体某些组成部分的基础 急性应激反应和应激诱导的可塑性 CRF 是与反复或慢性压力相关的精神症状的基础。 以下目标整合了不同的方法来检验这一假设。目标1： 将使用体内微透析和电生理学来阐明特定的 选择性激活 CRF-R1 与选择性激活 CRF-R1 的神经元和神经化学后果 DRN 内的 CRF-R2 受体。目标 2：将识别解剖基质 以及 CRF 对 DRN-5-HT 系统产生影响的电路 免疫组织化学、原位杂交和电子显微镜。目标 3： 将确定选择性激活 CRF-R1 与选择性激活 CRF-R1 的行为后果 DRN 内的 CRF-R2 受体。目标 4：将检查压力引起的适应 DRN-5-HT 系统关于 a) CRF 的作用，b) 底层 机制和 c) 神经化学适应是否与行为有关 适应（使用体内微透析、行为和受体 放射自显影）。我们之前的工作介绍了创新的想法 CRF-5-HT 相互作用是精神疾病的病理生理学焦点 和新型心理治疗药物的目标。拟议的研究将 从细胞到行为水平彻底表征这些相互作用。 因此，它们将增强我们对压力在疾病中的作用的理解。 精神病理学并指出治疗压力相关的新目标 精神疾病。