Rehabilitation of Stress-Induced Insomnia

压力引起的失眠的康复

• 批准号: 9062397
• 负责人: PINGFU FENG
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9062397
• 关键词: Acute; Address; Adult; Affect; Afghanistan; Agonist; Alcohol or Other Drugs use; Alcoholism; Animal Model; Animals; Antidepressive Agents; Anxiety Disorders; Behavior; Behavioral; Biology; Brain; Cardiovascular Diseases; Chronic; Chronic Insomnia; Chronic stress; Clinical; Clinical Management; Clinical Research; Clinical Trials; Collection; Comorbidity; Corticotropin-Releasing Hormone; Data; Disease; Dose; Drug Prescriptions; Drug Targeting; Drug usage; Eszopiclone; Evaluation; Exhibits; Extracellular Fluid; FDA approved; GABA Agonists; General Population; Goals; Government; Human; Hypertension; Hypothalamic structure; Impairment; Infusion procedures; Intervention; Iraq; Judgment; Knowledge; Lead; Learning; Link; Longitudinal Studies; Maintenance; Maternal Deprivation; Measurable; Medical; Memory; Mental Depression; Mental disorders; Microdialysis; Mission; Modeling; Molecular; Names; Neonatal; Neural Pathways; Neurobiology; Neurons; Obesity; Pathology; Pathway interactions; Patient Care; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Physiological; Polysomnography; Population; Post-Traumatic Stress Disorders; Prevalence; Procedures; Qualifying; Quality of life; Radioimmunoassay; Rattus; Recovery; Regulation; Rehabilitation therapy; Risk; Schizophrenia; Serotonin Antagonists; Severities; Sleep; Sleep Disorders; Sleeplessness; Soldier; Stress; Substance abuse problem; Syndrome; Techniques; Time; Tissues; Toxic effect; Trazodone; Treatment Efficacy; Treatment outcome; Tricyclic Antidepressive Agents; United States; Wakefulness; Work; abstracting; base; biological adaptation to stress; clinically significant; design; extracellular; genetic manipulation; human subject; hypnotic; hypocretin; improved; insight; interest; long-term rehabilitation; neurobiological mechanism; neurochemistry; neuropathology; novel marker; obesity risk; orexin A; pre-clinical; psychological distress; relating to nervous system; research study; response; sleep abnormalities; sleep regulation; targeted treatment; treatment duration; treatment effect; treatment strategy

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.

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。