Rehabilitation of Stress-Induced Insomnia

描述(由申请人提供)： 本项目的目的是评估和比较不同机制的催眠药急性治疗对改善睡眠和抑制脑内促肾上腺皮质激素释放激素(CRH)和食欲素水平的影响，以及长期使用几种不同的催眠药是否最终能改善慢性失眠大鼠的睡眠障碍和神经生物学异常。我们提出了两个目标，分别研究药物埃索匹龙(非苯二氮卓类GABA能激动剂)和曲唑酮(一种用于失眠的常用抗抑郁药)在急性(两天)治疗和慢性治疗(两周)中如何影响睡眠，以及这些药物是否直接通过急性脑灌注和间接通过慢性全身治疗抑制下丘脑CRH和食欲素。所有实验将在新生儿母体剥夺导致的慢性失眠大鼠模型上进行，并与对照组进行比较。将应用四项主要技术。这包括：(1)建立新生母体剥夺所致失眠的大鼠模型，(2)多导睡眠描记，这是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。临床意义本课题提出两个目标：回答不同类型催眠药短期或长期治疗能否恢复慢性失眠模型中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埃索匹松和曲唑酮治疗对睡眠和脑CRH和食欲素的即时和慢性影响，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。这些结果将有助于提高目前对慢性失眠治疗策略的理解。拟议工作与退伍军人事务部患者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，70%的创伤后应激障碍患者存在慢性失眠。它会导致第二天的功能受损和心理痛苦，并是后来抑郁风险增加的预测指标。食欲素能参与失眠症高觉醒的病理调控研究的圆满完成，将为失眠症的神经生物学调控提供重要的新见解，并可能为失眠症的治疗提供新的方向。

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.