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: 6836536
• 负责人: RITA VALENTINO
• 金额: $ 47.89万
• 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 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6836536
• 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）：皮质激素释放因子（CRF）和 血清素能（5-HT） - 反向raphe核（DRN）系统已经 独立于对压力和应力相关的急性反应 精神疾病（例如焦虑，抑郁症）。在过去的几年中， 我们提供了这两个系统在解剖学和功能上都是证据 与压力的响应有关。因此，我们证明了CRF调节DRN 急性的神经元活性和前脑靶标的5-HT释放 压力。此外，我们证明了重复的压力导致 DRN-5-HT系统的跨适应为CRF和随后的应力。这 指导这种竞争更新的假设是 DRN-5-HT系统是该行为肢体的某些组成部分的基础 急性应力反应以及应力诱导的可塑性在此功能中 CRF是与反复或慢性压力相关的精神病症状的基础。 以下目的是整合多种方法来检验该假设。目标1： 将使用体内微透析和电生理学来阐明特定 选择性激活CRF-R1 VS的神经化和神经化学后果。 DRN中的CRF-R2受体。目标2：将识别解剖基板 和CRF使用CRF影响DRN-5-HT系统的电路 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 VS的行为后果。 DRN中的CRF-R2受体。目标4：将检查压力引起的适应 关于a）CRF的作用的DRN-5-HT系统的 机制和c）神经化学适应是否是对行为的因果 适应（使用体内微透析，行为和受体 放射自显影）。我们以前的作品介绍了一个创新的想法， CRF-5-HT相互作用是精神疾病的病理生理重点 以及新型心理治疗剂的目标。拟议的研究将 从细胞到行为水平的这些相互作用彻底表征这些相互作用。 因此，他们将增强我们对压力在 精神病理学并指示治疗与压力有关的新目标 精神疾病。