Rehabilitation of Stress-Induced Insomnia

描述（由申请人提供）： 本研究的目的是评价和比较不同机制的催眠药的急性治疗如何改善睡眠和抑制促肾上腺皮质激素释放激素（CRH）和食欲素的脑水平，并评估用几种不同的催眠药进行长期治疗是否最终会使慢性失眠大鼠模型中的睡眠障碍和神经生物学异常恢复。我们提出了两个目的，分别研究药物右佐匹克隆（Lunesta，一种非苯二氮卓类GABA能激动剂）和曲唑酮（一种用于失眠的常用处方抗抑郁药）在急性（两天）治疗和慢性治疗（两周）中如何影响睡眠，以及这些药物是否通过急性脑灌注直接抑制下丘脑CRH和食欲素，并通过慢性全身治疗间接抑制。所有实验将在新生儿母亲剥夺诱导的慢性失眠大鼠模型中进行，并与对照受试者进行比较。将采用四大技术。这包括（1）我们的新生儿母亲剥夺诱导的失眠大鼠模型，（2）多导睡眠图记录，一种用于睡眠评估的经典技术，（3）用于细胞外液收集的微透析和（4）使用放射免疫测定来定量CRH和食欲素的水平。我们有足够的初步数据支持使用这些技术的可行性。临床意义我们提出本项目的两个目标：回答用不同类型的催眠药短期或长期治疗是否会恢复慢性失眠模型中的睡眠异常和神经生物学标志物的关键问题。该项目的成功完成将使我们能够概述右佐匹克隆和曲唑酮治疗对睡眠和大脑CRH和食欲素的即时和长期影响，并将这些药物对下丘脑CRH和食欲素的即时影响与失眠治疗的长期疗效相关联。这些结果将有助于改善目前对慢性失眠治疗策略的理解。拟议工作与VA患者护理使命的相关性失眠是美国普通人群中的常见疾病，70%的PTSD患者存在慢性失眠。它会导致第二天的功能受损和心理困扰，并且是后来抑郁风险增加的预测因素。食欲素能参与失眠症高觉醒病理调节的研究的成功完成将为失眠症的神经生物学调节提供重要的新见解，并可能为其治疗提供新的方向。 公共卫生相关性： 封管家：压力诱发失眠症的康复1拟议工作与退伍军人事务部病人护理使命的相关性失眠症是美国普通人群中的常见疾病，70%的PTSD患者存在慢性失眠症。它会导致第二天的功能受损和心理困扰，并且是后来抑郁风险增加的预测因素。虽然失眠是PTSD中最常见的睡眠障碍，但医生对其进行经验性治疗，对其相关神经生物学的了解有限。我们提出的评估MD大鼠模型的失眠可能满足需要一个合格的动物模型的纵向研究，分子研究，疗效和毒性的干预措施，针对觉醒/睡眠调节和失眠。我们提出了两个目标，这个项目：回答的关键问题，是否短期或长期治疗不同类型的催眠药将恢复睡眠和神经生物学标志物在慢性失眠模型的异常。成功完成拟议的研究不仅可以证实失眠症中过度觉醒的病理调节，而且还可以为失眠症的神经生物学调节提供重要的新见解，临床严重程度的新标志物，以及直接或间接治疗的神经通路的新见解。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Feng: Rehabilitation of Stress-Induced Insomnia 1 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. Although insomnia is the most commonly encountered sleep disorder in PTSD, medical practitioners treat it empirically and have a limited understanding of its relevant neurobiology. Our proposed evaluation of the MD rat model of insomnia may satisfy the need for a qualified animal model for longitudinal studies, molecular studies, and efficacy and toxicity of interventions directed at wake/sleep regulation and insomnia. 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. Successful completion of the proposed studies may confirm not only pathological regulation of hyperarousal in insomnia but also provide important new insights into the neurobiological regulation of insomnia, new markers for clinical severity, and new insights into neural pathways for direct or adjunctive treatment.