Rehabilitation of Stress-Induced Insomnia

冯，应激性失眠的康复1 摘要 该项目的目标是评估和比较使用催眠药进行的急性治疗 不同的机制可以改善睡眠和抑制大脑促肾上腺皮质激素释放激素的水平 (CRH)和食欲素参与失眠的神经生物学病理，并评估是否 使用几种不同的催眠药进行长期治疗，最终将使睡眠障碍和 慢性失眠大鼠模型的神经生物学异常。我们分别提出了两个目标 研究药物埃佐匹克隆(LUNESTA，一种非苯二氮类GABA能激动剂)和曲唑酮(a 常用于治疗失眠的抗抑郁药)在急性(两天)治疗和慢性治疗中影响睡眠 治疗(两周)，以及这些药物是否直接通过急性脑抑制下丘脑CRH和食欲素 通过输液和间接的慢性系统治疗。所有实验将在慢性阻塞性肺疾病大鼠模型中进行。 新生儿母体剥夺所致失眠与对照组的比较。四大 将应用各种技术。这包括(1)给我们一个由新生儿母体引起的失眠的大鼠模型。 剥夺，(2)多导睡眠图记录，一种经典的睡眠评估技术，(3)微透析 收集细胞外液；(4)用放射免疫法测定CRH和食欲素水平。我们有 充分的初步数据支持使用这些技术的可行性。 临床意义： 我们为这个项目提出了两个目标：回答短期或长期的关键问题 不同类型的催眠药治疗可恢复睡眠和神经生物学的异常 慢性失眠模型中的标志物。项目的成功完成将使我们能够勾勒出 埃索匹龙和曲唑酮治疗对睡眠和脑CRH的即刻和慢性影响 Orexins，并将这些药物对下丘脑CRH的即刻作用和Orexins与Long 失眠治疗的远期疗效。这些结果将有助于改善目前的理解 在慢性失眠的治疗策略中。 拟议工作与退伍军人管理局病人护理任务的相关性 失眠是美国普通人群中的一种常见疾病，慢性失眠在美国 70%的创伤后应激障碍患者。它会导致第二天的功能受损和心理痛苦，并且是一个预测因子 后来抑郁风险增加的可能性。成功地完成了食欲素能参与中枢神经系统的研究 失眠症高觉醒的病理调控将为神经生物学提供重要的新见解 调节失眠，并可能为其治疗提供新的方向。

Feng, Rehabilitation of Stress-Induced Insomnia 1 Abstract The goal of this project is to evaluate and compare how the acute treatment with hypnotics that have different mechanisms would improve sleep and suppress the brain levels of corticotropin-releasing hormone (CRH) and the orexins which are involved in the neurobiological pathology for insomnia, and to evaluate whether a long term treatment with several different hypnotics would eventually rehabilitate both the sleep disorder and the neurobiological abnormalities in a chronic rat model of insomnia. We propose two objectives to separately study how the drugs eszopiclone (Lunesta, a non-benzodiazepine GABAergic agonist) and trazodone (a commonly prescribed antidepressant used for insomnia) affect sleep in acute (two days) treatment and chronic treatment (two weeks), and whether these drugs suppress hypothalamic CRH and orexins directly by acute brain infusion and indirectly by chronic systemic treatment. All experiment will be conducted in a rat model of chronic insomnia induced by neonatal maternal deprivation in comparison to that in control subjects. Four major techniques will be applied. This includes (1) to us a rat model of insomnia induced by the neonatal maternal deprivation, (2) polysomnographic recording, a classic technique for sleep evaluation, (3) microdialysis for extracellular fluid collection and (4) use radioimmunoassay to quantify the levels of CRH and orexins. We have sufficient preliminary data in support of the feasibility of using these techniques. Clinical significance： We propose two objectives for this project: to answer the key questions of whether short term or long term treatment with different types of hypnotics would recover the abnormalities of sleep and the neurobiological markers in the chronic model of insomnia. The successful completion of the project would allow us to outline the immediate and the chronic effects of treatment with eszopiclone and trazodone on sleep and brain CRH and the orexins, and to correlate the immediate effect of these drugs on hypothalamic CRH and the orexins with the long term efficacy of insomnia treatment. These results would be able to help in improving the current understanding in the treatment strategy for chronic insomnia. Relevance of the Proposed Work to the VA Patient Care Mission Insomnia is a common disorder in the general population in the United States and chronic insomnia is present in 70% of those with PTSD. It leads to impaired next-day functioning and psychological distress, and is a predictor of later increased depression risk. Successful completion of the study of orexinergic involvement in the pathological regulation of hyperarousal in insomnia will provide important new insights into the neurobiological regulation of insomnia, and may provide new directions for its treatment.