Neuroendocrine Regulation of Sleep in PTSD

PTSD 患者睡眠的神经内分泌调节

• 批准号: 7059852
• 负责人: Thomas C Neylan
• 金额: $ 45.48万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-29 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059852
• 关键词: adrenocorticotropic hormone; clinical research; corticotropin releasing factor; cortisol; electroencephalography; hormone metabolism; hormone regulation /control mechanism; human subject; metyrapone; neuroendocrine system; photon absorptiometry; polysomnography; posttraumatic stress disorder; sleep; somatotropin; stressor

DESCRIPTION (provided by applicant): This new R01 proposal will examine neuroendocrine factors mediating sleep disturbances in men and women with chronic Posttraumatic Stress Disorder (PTSD). We previously demonstrated that; 1) metyrapone administration, which blocks adrenal cortisol synthesis and stimulates the release of hypothalamic Corticotropin Releasing Factor (CRF), resulted in a decrease in sleep time, an increase in awakenings, and a robust decrease in quantitative delta sleep in both PTSD and control subjects; 2) The sleep and endocrine (increase in ACTH) responses to metyrapone were significantly decreased in PTSD suggesting diminished sensitivity to CRF challenge; and 3) The metyrapone-related disruption to sleep was predicted by the increase in ACTH measured the following morning. These findings strongly suggest that the CRF response to metyrapone accounts for the observed disruption to sleep. This data is consistent with an extensive literature in animal studies documenting the role of CRF in mediating arousal responses and sleep fragmentation. The proposed study will test the hypothesis that the immediate endocrine response to metyrapone challenge accounts for the observed disruption in total sleep time and quantitative delta sleep. This will be accomplished by repeated sampling of nocturnal hormone activity during the sleep recordings both before and after metyrapone administration. Further, given the known relationship between delta sleep and growth hormone (GH) release, and the fact that CRF release suppresses GH, we will measure GH responses to metyrapone to add a convergent test of the role of CRF in disrupting sleep. Finally, given that there are important gender differences in sleep, HPA, and somatotropic axis function, we will examine if gender affects the response of sleep to a CRF manipulation. We will compare immediate nocturnal cortisol, 11 deoxycortisol, ACTH, and GH responses to metyrapone in a 2x2 design crossing group status (PTSD vs controls) and gender (half men/half women). We will study medication-free, medically healthy, non-obese, non-substance abusing men and women ages 20 to 50 with chronic PTSD versus normal controls. Three nights of polysomnography with nocturnal blood sampling (night 1= adaptation, nights 2-3= pre and post metyrapone administration) will be conducted on the General Clinical Research Center at the University of California, San Francisco. The focus on the role of CRF in mediating disturbed sleep in PTSD has broader implications for understanding the mechanism of disturbed sleep found in normal subjects responding to acute and chronic stressors. This proposal will also be the first study to examine gender effects on sleep and HPA ever conducted in the PTSD field. Finally, the results from the study have implications for the clinical applicability of CRF receptor antagonists, which continue to be developed.

描述（由申请人提供）：这项新的 R01 提案将检查介导患有慢性创伤后应激障碍 (PTSD) 的男性和女性睡眠障碍的神经内分泌因素。我们之前证明了； 1) 美替拉酮可阻断肾上腺皮质醇合成并刺激下丘脑促肾上腺皮质激素释放因子 (CRF) 的释放，导致 PTSD 受试者和对照受试者的睡眠时间减少、觉醒次数增加以及 Delta 睡眠定量大幅减少； 2) PTSD 患者对美替拉酮的睡眠和内分泌（ACTH 增加）反应显着降低，表明对 CRF 挑战的敏感性降低； 3) 通过第二天早上测量的 ACTH 的增加来预测与美替拉酮相关的睡眠中断。这些发现强烈表明，CRF 对美替拉酮的反应是观察到的睡眠中断的原因。该数据与大量动物研究文献一致，这些文献记录了 CRF 在介导唤醒反应和睡眠碎片化方面的作用。拟议的研究将检验以下假设：对美替拉酮挑战的直接内分泌反应解释了观察到的总睡眠时间和定量增量睡眠的中断。这将通过在甲吡酮给药之前和之后的睡眠记录期间重复采样夜间激素活性来实现。此外，考虑到 Delta 睡眠和生长激素 (GH) 释放之间的已知关系，以及 CRF 释放抑制 GH 的事实，我们将测量 GH 对美替拉酮的反应，以添加 CRF 在扰乱睡眠中的作用的聚合测试。最后，鉴于睡眠、HPA 和生长轴功能存在重要的性别差异，我们将检查性别是否影响睡眠对 CRF 操作的反应。我们将在跨组状态（PTSD 与对照组）和性别（一半男性/一半女性）的 2x2 设计中比较即时夜间皮质醇、11 脱氧皮质醇、ACTH 和 GH 对美替拉酮的反应。我们将研究不服用药物、身体健康、不肥胖、不滥用药物的 20 至 50 岁患有慢性 PTSD 的男性和女性与正常对照组的比较。三个晚上的多导睡眠监测和夜间血液采样（第 1 晚 = 适应，第 2-3 晚 = 美替拉酮给药前后）将在旧金山加利福尼亚大学综合临床研究中心进行。 关注 CRF 在调节 PTSD 睡眠障碍中的作用对于理解正常受试者对急性和慢性压力源的反应中发现的睡眠障碍机制具有更广泛的意义。该提案也将是在 PTSD 领域开展的第一项研究性别对睡眠和 HPA 影响的研究。最后，该研究的结果对持续开发的 CRF 受体拮抗剂的临床适用性具有影响。