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：（改编自申请人的摘要） 促肾上腺皮质激素释放因子（CRF）和血清素（5-HT）系统 独立涉及与压力相关的精神疾病。 我们证明了 CRF 对前脑 5-HT 释放的有效影响 推定的 5-HT 中缝背核 (DRN) 神经元的活性。拍摄于 DRN 中 CRF 神经支配和 CRF 受体表达的发现， 这些结果表明内源性 CRF 在 DRN 内发挥作用 调节前脑5-HT功能。以下 AIMS 对此进行测试 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， 识别参与这些相互作用的条件，并确定 DRN 内的 CRF 效应是否在相关行为中发挥作用 患有抑郁症。 1) 表征和量化 CRF 对 终末区细胞外 5-HT 水平和 DRN 神经元活动。 将生成 CRF 效应的剂量反应曲线（施用 静脉注射或中缝内）对侧隔膜、杏仁核和 5-HT 释放的影响 皮质和 DRN 神经元活动。 CRF拮抗剂的功效 （静脉注射、全身或中缝内给药）以预防这些 效果将被确定。该 AIM 将揭示 CRF 是否起作用 直接在 DRN 内改变前脑 5-HT 释放，是否有影响 5-HT 释放具有区域特异性，且 CRF 受体亚型 涉及; 2）确定内源性的生理条件 CRF 对 DRN-5-HT 系统的影响。 CRF拮抗剂的能力 （静脉注射或中缝注射）以防止前脑 5-HT 发生变化 由不同的挑战引起的释放将被确定。这个目标 将揭示 CRF-5-HT 相互作用发生的条件； 3) 表征 DRN 中 CRF-5-HT 相互作用的细胞底物 并识别 DRN 的 CRF 传入。 CRF 之间的相互作用 DRN 中的终端和 5-HT 进程将在 使用双标记免疫组织化学和电子的超微结构水平 显微镜。神经元束追踪将用于识别 CRF 传入 DRN。该目标将揭示潜在的细胞机制 潜在的 CRF-5-HT 相互作用，并提供详细说明 CRF 如何进行的图 系统链接至 DRN； 4) 阐明CRF-5-HT相互作用的作用 与抑郁症相关的行为。假设 CRF DRN 中的释放和随后的 5-HT 前脑释放抑制 与游泳压力相关的行为不活动的基础将是 已测试。 CRF 或 CRF 拮抗剂（静脉注射或 中缝内）对强迫游泳测试中行为的影响将被确定。这 AIM 将揭示 CRF-5HT 潜在的病理生理学后果 互动。