NEUROENDOCRINE ASPECTS OF DEPRESSIVE ILLNESS

抑郁症的神经内分泌方面

• 批准号: 3069937
• 负责人: RUSSELL Elliott POLAND
• 金额: $ 6.42万
• 依托单位: LOS ANGELES COUNTY HARBOR-UCLA MED CTR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3069937
• 关键词: REM sleep; adrenocorticotropic hormone; anticholinergic agent; bioassay; central nervous system disorders; cortisol; dexamethasone; electroencephalography; human subject; mental disorder diagnosis; neural information processing; neural transmission; neurotransmitters; pituitary adrenal axis; radioimmunoassay; serotonin; sleep regulatory center

It is well established that abnormalities of the hypothalamic- pituitary-adrenal cortical (HPA) axis and sleep EEG parameters occur frequently in patients with major depression, endogenous and/or melancholic subtype. However, the reasons for and the mechanisms underlying these abnormalities remain obscure. The experiments outlined in this ADAMHA RSDA Level II application are designed to address fundamental issues related to the abnormalities of these physiologic systems. First, I plan to show that plasma ACTH and cortisol hypersecretion are synonymous with DST nonsuppression and not manifestations of two different abnormalities of the HPA axis. Second, I plan to show that DST nonsuppression is a pituitary-associated phenomena in that cortisol elevations are a consequence of increased ACTH secretion. To do so, I plan to concurrently measure both biologically and immunologically active plasma ACTH concentrations in plasma samples obtained at frequent intervals during the night under basal conditions and also after DEX administration. Third, I plan to test the hypothesis that ACTH hypersecretion/DST nonsuppression and reduced REM latency are closely linked within subjects, possibly on the basis of a common CNS abnormality underlying the dysregulation of both physiologic systems. The CNS neurotransmitter systems which might regulate both the HPA axis and REM sleep parameters will be studied with pharmacologic challenges. Normal volunteers and then patients will be given cholinegic (Ach) and serotinergic (5- HT) antagonists prior to or during sleep, and the expected reduction in nocturnal ACTH and cortisol secretion will be correlated with the degree of REM latency increase. Similarly, by the repeated administration of Ach and 5-TH antagonists, I will attempt to reproduce the REM latency and HPA axis abnormalities in normal volunteers. These challenge experiments will help to identify particular CNS neurotransmitter systems involved in the REM sleep and HPA abnormalities and to eventually establish neurotransmitter hierarchies (linkages) which underlie the regulation of these two physiologic systems in normals and depressed patients. As a complement to the human studies, studies in animals also will be performed to determine the neurotransmitter linkages associated with the regulation of the HPA axis. As a whole, both the human and animal studies will help to elucidate the neurochemical substrates and the physiologic significance of HPA axis and REM sleep abnormalities observed in patients with depression.

众所周知，下丘脑的异常 垂体 - 肾上腺皮质（HPA）轴和睡眠EEG参数 经常发生在严重抑郁，内源性的患者中 和/或忧郁的亚型。 但是，原因和 这些异常的机制仍然晦涩难懂。 这 此Adamha RSDA II级应用中概述的实验 旨在解决与 这些生理系统的异常。 首先，我打算展示 血浆ACTH和皮质醇超乳清分泌是同义词 用DST非抑制，而不是两种不同的表现 HPA轴异常。 第二，我打算证明DST 非抑制是一种与垂体相关的现象 皮质醇抬高是ACTH增加的结果 分泌。 为此，我计划同时测量 具有生物学和免疫学活性血浆ACTH 频繁间隔获得的血浆样品浓度 在夜晚，在基础条件下以及dex之后 行政。 第三，我计划检验Acth的假设 过度分泌/DST非抑制和减少的REM潜伏期为 在受试者中密切相关，可能是基于共同的 中枢神经系统异常是两种生理的失调的基础 系统。 CNS神经递质系统可能 调节HPA轴和REM睡眠参数将是 研究了药理挑战。 正常的志愿者和 然后，将给予患者胆碱（ACH）和5-羟色胺能（5- ht）在睡眠之前或睡眠期间的拮抗剂和预期的 夜间ACTH和皮质醇分泌的降低将是 与REM潜伏期的增加相关。 相似地， 通过反复的ACH和第5-拮抗剂的给药，我将 尝试重现REM潜伏期和HPA轴 正常志愿者的异常。 这些挑战实验 将有助于识别特定的CNS神经递质系统 参与REM睡眠和HPA异常以及 最终建立神经递质层次结构（链接） 基于这两个生理系统的调节 正常患者和抑郁症患者。 作为对人类的补充 研究，还将对动物进行研究以确定 与调节有关的神经递质联系 HPA轴。 总体而言，人类和动物研究都将 有助于阐明神经化学底物和生理 HPA轴和REM睡眠异常的重要性 抑郁症患者。