Neuroendocrine Regulation of Sleep in PTSD

描述(申请人提供)：这份新的R01提案将研究慢性创伤后应激障碍(PTSD)男性和女性睡眠障碍的神经内分泌因素。我们先前证实：1)在PTSD和对照组中，服用美曲酮可以阻止肾上腺皮质醇的合成并刺激下丘脑促肾上腺皮质激素释放因子(CRF)的释放，导致睡眠时间减少，觉醒次数增加，定量增量睡眠显著减少；2)PTSD患者对美曲酮的睡眠和内分泌(ACTH增加)反应显著减少，这表明PTSD对CRF挑战的敏感性降低；以及3)通过第二天早上测量的ACTH增加，可以预测与美曲酮相关的睡眠干扰。这些发现有力地表明，CRF对甲替拉奉的反应是观察到的睡眠中断的原因。这一数据与动物研究中的大量文献一致，这些文献记录了CRF在调节唤醒反应和睡眠碎片中的作用。这项拟议的研究将检验这样一种假设，即对甲替拉奉挑战的即时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。这将通过在给药前后的睡眠记录中重复采样夜间激素活动来实现。此外，考虑到增量睡眠和生长激素(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对甲替拉奉的反应，以增加CRF在扰乱睡眠中的作用的收敛测试。最后，鉴于在睡眠、HPA和促生长轴功能方面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2x2设计中比较夜间皮质醇、11脱氧皮质醇、促肾上腺皮质激素和生长激素对甲孕酮的反应，交叉分组(创伤后应激障碍与对照组)和性别(男性/女性各半)。我们将研究20至50岁的慢性创伤后应激障碍患者与正常对照组的非药物治疗、医学健康、非肥胖、非物质滥用的男性和女性。将在加州大学旧金山分校的综合临床研究中心进行三个晚上的多导睡眠监测和夜间采血(夜间1=适应，夜间2-3=服用美托拉酮前后)。 对CRF在创伤后应激障碍中调节睡眠障碍的作用的关注，对于理解正常受试者对急性和慢性应激反应的睡眠障碍的机制具有更广泛的意义。这项提案也将是在创伤后应激障碍领域进行的第一项关于性别对睡眠和HPA影响的研究。最后，这项研究的结果对CRF受体拮抗剂的临床适用性有一定的意义，该受体拮抗剂正在继续开发中。

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.