Neuroendocrine Regulation of Sleep in PTSD

描述（由申请人提供）：这一新的R 01提案将研究慢性创伤后应激障碍（PTSD）男性和女性中调节睡眠障碍的神经内分泌因素。我们以前证明过; 1）甲吡酮给药，其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和对照受试者的睡眠时间减少，觉醒增加，以及定量δ睡眠的强烈减少;（2）睡眠与内分泌（ACTH增加）对甲吡酮的反应在PTSD中显著降低，表明对CRF激发的敏感性降低;和3）通过第二天早上测量的ACTH的增加来预测与甲吡酮相关的睡眠中断。这些发现强烈表明，CRF对甲吡酮的反应解释了观察到的睡眠中断。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片段化中的作用。拟议的研究将检验以下假设：对甲吡酮激发的即时内分泌反应解释了观察到的总睡眠时间和定量δ睡眠的中断。这将通过在给予甲吡酮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δ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对甲吡酮的反应，以增加CRF在扰乱睡眠中的作用的收敛测试。最后，鉴于睡眠、HPA和促生长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。我们将比较立即夜间皮质醇，11脱氧皮质醇，促肾上腺皮质激素和生长激素的反应，甲吡酮在2x2设计交叉组状态（创伤后应激障碍与对照组）和性别（一半男性/一半女性）。我们将研究无药物治疗，医学健康，非肥胖，非物质滥用的男性和女性，年龄在20至50岁之间的慢性PTSD与正常对照组。将在加州大学旧金山分校的综合临床研究中心进行三晚的多导睡眠监测和夜间血液采样（第1晚=适应，第2-3晚=甲吡酮给药前后）。弗朗西斯科。 关注CRF在PTSD中介导睡眠障碍的作用，对于理解正常受试者对急性和慢性应激源的反应中发现的睡眠障碍机制具有更广泛的意义。这项提案也将是第一项研究性别对睡眠和HPA的影响，在PTSD领域进行过。最后，研究结果对CRF受体拮抗剂的临床适用性有影响，CRF受体拮抗剂仍在开发中。

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.