Neuroendocrine Regulation of Sleep in PTSD

描述（由申请人提供）：这个新的R01提案将研究神经内分泌因子介导慢性创伤后应激障碍（PTSD）男性和女性的睡眠障碍。我们之前证明过；1)使用美吡酮阻断肾上腺皮质醇合成，刺激下丘脑促肾上腺皮质激素释放因子（CRF）的释放，导致PTSD和对照组受试者睡眠时间减少，觉醒次数增加，定量delta睡眠明显减少；2) PTSD患者对美吡酮的睡眠和内分泌（ACTH升高）反应显著降低，提示对CRF刺激的敏感性降低；3)通过第二天早晨测量的ACTH升高预测美替拉酮相关的睡眠中断。这些发现有力地表明，CRF对metyrapone的反应是观察到的睡眠中断的原因。这一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分裂中的作用。拟议的研究将验证一种假设，即对美吡酮的直接内分泌反应是观察到的总睡眠时间和定量delta睡眠中断的原因。这将通过在给药前后对睡眠记录期间的夜间激素活动进行重复采样来完成。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metyrapone的反应，以增加CRF在干扰睡眠中的作用的收敛测试。最后，考虑到睡眠、HPA和体适性轴功能存在重要的性别差异，我们将研究性别是否影响睡眠对CRF操作的反应。我们将比较在2x2设计的跨组状态（PTSD vs对照组）和性别（男女各占一半）中，即刻夜间皮质醇、11 -去氧皮质醇、ACTH和GH对metyrapone的反应。我们将研究20至50岁的无药物、医学健康、非肥胖、非药物滥用的慢性创伤后应激障碍男性和女性与正常对照。将在加州大学旧金山分校的普通临床研究中心进行三晚的多导睡眠仪和夜间采血（第1晚=适应，第2-3晚=给药前后）。

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.