CORTICOTROPIN RELEASING FACTOR/SEROTONERGIC INTERACTIONS

促肾上腺皮质激素释放因子/血清素相互作用

• 批准号: 2757947
• 负责人: RITA VALENTINO
• 金额: --
• 依托单位: ALLEGHENY UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1998-12-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2757947
• 关键词: afferent nerve; behavior test; behavioral /social science research tag; brain mapping; corticotropin releasing factor; depression; dorsal raphe nucleus; electrophysiology; extracellular; hormone regulation /control mechanism; immunocytochemistry; laboratory rat; neurochemistry; neuropathology; neurotransmitter transport; oral behavior; prosencephalon; serotonin; stress

DESCRIPTION: (Adapted From The Applicant's Abstract) Corticotropin-releasing factor (CRF) and serotonin (5-HT) systems have been independently implicated in stress-related psychiatric disorders. We demonstrate potent effects of CRF on forebrain 5-HT release and activity of putative 5-HT dorsal raphe nucleus (DRN) neurons. Taken with findings of CRF innervation and expression of CRF receptors in the DRN, these results suggest that endogenous CRF acts within the DRN to regulate forebrain 5-HT function. The following AIMS test this hypothesis by characterizing CRF-5-HT interactions at an ultrastructural, electrophysiological and neurochemical level, identifying conditions that engage these interactions, and determining whether CRF effects within the DRN play a role in a behavior associated with depression. 1) Characterize and quantify CRF effects on extracellular 5-HT levels in terminal regions and DRN neuronal activity. Dose-response curves will be generated for CRF effects (administered i.c.v. or intraraphe) on 5-HT release in lateral septum, amygdala and cortex and DRN neuronal activity. The efficacy of CRF antagonists (administered i.c.v., systemically or intraraphe) to prevent these effects will be determined. This AIM will reveal whether CRF acts directly within the DRN to alter forebrain 5-HT release, whether effects on 5-HT release are regionally specific and the CRF receptor subtype involved; 2) Identify physiological conditions during which endogenous CRF impacts on DRN-5-HT systems. The ability of CRF antagonists (administered i.c.v. or intraraphe) to prevent changes in forebrain 5-HT release elicited by different challenges will be determined. This AIM will reveal conditions during which CRF-5-HT interactions are engaged; 3) Characterize cellular substrates for CRF-5-HT interactions in the DRN and identify CRF afferents to the DRN. Interactions between CRF terminals and 5-HT processes in the DRN will be visualized at the ultrastructural level using dual label immunohistochemistry and electron microscopy. Neuronal tract tracing will be used to identify CRF afferents to the DRN. This AIM will reveal potential cellular mechanisms underlying CRF-5-HT interactions and provide a map detailing how CRF systems link to the DRN; 4) Elucidate the role of CRF-5-HT interactions in a behavior associated with depression. The hypothesis that CRF release in the DRN and subsequent inhibition of 5-HT forebrain release underlie behavioral immobility associated with swim stress will be tested. The effects of CRF or CRF antagonists (administered i.c.v. or intraraphe) on behavior in the forced swim test will be determined. This AIM will reveal potential pathophysiological consequences of CRF-5HT interactions.

描述：（根据申请人的摘要改编） 皮质激素释放因子（CRF）和5-羟色胺（5-HT）系统具有 独立于与压力有关的精神病障碍。 我们证明了CRF对前脑5-HT释放的有效影响，并且 推定的5-HT背raphe核（DRN）神经元的活性。与 CRF神经的发现和CRF受体在DRN中的表达， 这些结果表明内源性CRF在DRN内作用 调节前脑5-HT功能。以下目标测试 通过表征CRF-5-HT相互作用的假设 超微结构，电生理和神经化学水平， 确定参与这些互动并确定的条件 DRN中的CRF效应是否在相关的行为中起作用 抑郁。 1）表征并量化CRF对 末端区域和DRN神经元活性的细胞外5-HT水平。 将生成CRF效应的剂量响应曲线（管理 I.C.V.或在侧隔，杏仁核和 皮质和DRN神经元活性。 CRF拮抗剂的功效 （在系统或内部的I.C.V.管理）以防止这些 将确定效果。这个目标将揭示CRF是否行动 直接在DRN内改变前脑5-HT释放，是否影响 5-HT释放在区域特异性和CRF受体亚型 涉及; 2）确定内源性的生理条件 CRF会影响DRN-5-HT系统。 CRF拮抗剂的能力 （管理I.C.V.或Intraraphe）以防止前脑5-HT变化 将确定由不同挑战引起的发布。这个目标 将揭示CRF-5-HT相互作用的条件； 3）表征DRN中CRF-5-HT相互作用的细胞底物 并确定DRN的CRF传入。 CRF之间的相互作用 DRN中的终端和5-HT过程将在 使用双标签免疫组织化学和电子的超微结构水平 显微镜。神经元路跟踪将用于识别CRF DRN的传入。这个目标将揭示潜在的细胞机制 CRF-5-HT相互作用的基础，并提供了一个详细说明CRF的地图 系统链接到DRN； 4）阐明CRF-5-HT相互作用的作用 与抑郁症相关的行为。 CRF的假设 在DRN中释放并随后抑制5-HT前脑释放 与游泳压力相关的行为不动的基础将是 测试。 CRF或CRF拮抗剂的作用（管理I.C.V.或 将确定强制游泳测试中的行为内部图。这 AIM将揭示CRF-5HT的潜在病理生理后果 互动。