MODEL OF HYPERCORTISOLISM FOR MAJOR DEPRESSIONS

严重抑郁症的皮质醇增多症模型

• 批准号: 2890460
• 负责人: ALAN F. SCHATZBERG
• 金额: $ 50.13万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2890460
• 关键词: Saimiri; adrenocorticotropic hormone; animal developmental psychology; behavior test; behavioral /social science research tag; brain metabolism; clinical research; corticotropin releasing factor; cortisol; dexamethasone; homovanillate; hormone regulation /control mechanism; human subject; hypercortisolism; longitudinal animal study; major depression; metyrapone; neuroendocrine system; pituitary gland; psychological models; psychosocial separation; radioimmunoassay

DESCRIPTION (Adapted from applicant's abstract): This research investigates three process-oriented hypotheses about the neurobiology of hypercortisolism during major depressions in humans using a model of hypercortisolism in monkeys. The first proposed process involves changes in adrenal responsiveness to the adrenocorticotropic hormone (ACTH). Recent accounts derived from clinical reports suggest that hypersecretion of cortisol in depressed human patients is initially driven by hypersecretion of ACTH. With prolonged depressions, however, cortisol levels remain elevated while ACTH levels are reduced. Apparently hypercortisolism is maintained, despite reductions in ACTH, because adrenal responsiveness to ACTH is enhanced. If this time-dependent process likewise occurs during social separation induced hypercortisolism in squirrel monkeys, then normal adrenal responses are expected in monkeys tested after acute separations, whereas adrenal hyper-responsiveness to ACTH is expected after chronic separations. To determine whether hyper-responsiveness is due to corticotropin releasing hormone (CRH) and/or ACTH potentiation effects on the adrenal cortex, ACTH stimulation tests will also be administered after chronic separations to dexamethasone pretreated monkeys. The second proposed process involves changes in pituitary responsiveness to the ACTH-releasing hormone CRH. Research suggests that pituitary corticotrophs in depressed human patients are initially stimulated by excessive hypothalamic CRH, but with prolonged depressions this stimulatory effect on the pituitary is suppressed by high circulating levels of cortisol. If a similar process occurs in the investigator's model of hypercortisolism in monkeys, then normal responses to CRH are expected after acute separations, whereas pituitary hypo-responsiveness to CRH is expected after chronic separations. To determine whether hypo-responsiveness to CRH is due to corticosteroid feedback on pituitary corticotrophs, CRH stimulation tests will also be administered after chronic separations to metyrapone pretreated monkeys. The third proposed process involves corticosteroid induced increases in central and peripheral measures of dopamine. Relative to nonpsychotic depressed patients or healthy human volunteers, major depressed patients that develop psychotic features typically show higher cortisol levels, higher plasma free dopamine levels, and higher plasma and cerebrospinal fluid (CSF) levels of the dopamine metabolite homovanillic acid (HVA). In squirrel monkeys, hypersecretion of cortisol is likewise associated with increases in plasma and CSF HVA, but not CSF levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenleneglycol (MHPG). Long-lasting increases in cortisol are apparent within hours of separation, whereas increases in HVA occur late (1-3 days post-separation) and persist for several days. This time course is consistent classic mechanisms of steroid hormone action on protein synthesis, and concurs with clinical reports that neuroendocrine stimulation tests that activate the hypothalamic-pituitary-adrenal (HPA) axis produce delayed increases in HVA, but not MHPG, in healthy human volunteers. In the proposed research, squirrel monkey cortisol, ACTH and HVA responses to direct stimulation of adrenocortical activity by synthetic ACTH, and indirect stimulation by synthetic oCRH, will be compared with neuroendocrine time course data collected from psychotic depressed patients, nonpsychotic depressed patients, and healthy human volunteers. These comparative longitudinal analyses provide unique opportunities to characterize the validity of the model with respect to clinical subtypes, and will therefore follow as closely as possible the doses of bioactive substances, their time of administration, and the sample collection schedules used in the investigator's ongoing studies of HPA dysregulation during major depressive disorders in humans.

描述（根据申请人的摘要改编）：这项研究调查了 关于高皮质醇的神经生物学的三个以过程为导向的假设 在人类的重大凹陷期间，使用过度皮质醇模型 猴子。 第一个提出的过程涉及肾上腺的变化 对肾上腺皮质激素（ACTH）的反应。 最近的帐户 从临床报告中得出的表明，皮质醇在 抑郁症患者最初是由ACTH的过度分泌驱动的。 但是，随着抑郁的长时间，皮质醇水平保持升高，而 ACTH水平降低。 尽管 ACTH的减少，因为对ACTH的肾上腺反应性得到增强。 如果 这个时间依赖的过程同样发生在社会分离期间 松鼠猴中的超皮质醇，那么正常的肾上腺反应为 急性分离后测试的猴子预期 慢性分离后，预计对ACTH的高反应性。 到 确定过度反应性是否是由于皮质激素释放引起的 激素（CRH）和/或ACTH增强对肾上腺皮质，ACTH的影响 慢性分离后，还将进行刺激测试 地塞米松预处理猴子。 第二个提出的过程涉及 垂体释放激素CRH的垂体反应性的变化。 研究表明，抑郁症患者的垂体皮质营养 最初由下丘脑CRH刺激，但长期 抑郁症对垂体的这种刺激作用被高抑制 循环水平的皮质醇水平。 如果在 研究者在猴子中的高皮质醇的模型，然后是正常反应 急性分离后，预计CRH是垂体 慢性分离后，预计对CRH的反应性低。 到 确定对CRH的低反应性是否是由于皮质类固醇引起的 垂体皮质营养物，CRH刺激测试的反馈也将是 在慢性分离与甲吡酮预处理的猴子后进行给药。 提出的第三个过程涉及皮质类固醇引起的增加 多巴胺的中央和外围测量。 相对于非精神病 抑郁症患者或健康的人类志愿者，主要抑郁症患者 发展精神病特征通常显示出较高的皮质醇水平， 较高的缺乏血浆多巴胺水平以及较高的血浆和脑脊 多巴胺代谢产物同甲基酸（HVA）的流体（CSF）水平。 在 松鼠猴子，皮质醇的过度分泌同样与 血浆和CSF HVA的增加，但不增加了去甲肾上腺素的CSF水平 代谢产物3-甲氧基-4-羟基苯乙烯（MHPG）。 持久增加 在皮质醇中，在分离后的几小时内显而易见，而增加 HVA发生迟到（分离后1-3天），并持续几天。 这种时间课程是类固醇激素作用的一致经典机制 关于蛋白质合成，并与神经内分泌的临床报道同意 激活下丘脑 - 垂体 - 肾上腺（HPA）的刺激测试 健康人的HVA（而不是MHPG）的轴延迟增加而不是MHPG 志愿者。 在拟议的研究中，松鼠猴皮质醇，ACTH和 HVA对直接刺激肾上腺皮质活性的反应 ACTH和合成OCRH的间接刺激将与 从精神病患者收集的神经内分泌时间课程数据， 非精神病患者和健康的人类志愿者。 这些 比较纵向分析为 表征模型相对于临床亚型的有效性， 因此，将尽可能接近生物活性剂量 物质，管理时间和样本收集 研究人员正在进行的HPA失调研究中使用的时间表 在人类的主要抑郁症中。