Rehabilitation of Stress-Induced Insomnia

压力引起的失眠的康复

• 批准号: 7750272
• 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: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750272
• 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 Delivery Systems; Drug Prescriptions; 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; neurobiological mechanism; neurochemistry; neuropathology; novel marker; obesity risk; orexin A; pre-clinical; psychological distress; public health relevance; relating to nervous system; research study; response; sleep abnormalities; sleep regulation; 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. 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.

描述（由申请人提供）： 冯，康复压力引起的失眠1摘要该项目的目的是评估和比较具有不同机制的急性治疗如何改善睡眠并抑制抑制促肾上腺皮质激素的激素的大脑水平，并与脑中的病理学相关的多种病理学的疾病，以及对昏迷的病理学的疾病，以及对昏迷的病理学作用，以及对昏迷的病理学的疾病，是否涉及一定程度的病理学。在慢性大鼠失眠模型中同时恢复睡眠障碍和神经生物学异常。我们提出了两个目标，以分别研究药物如何（lunesta，一种非苯并二氮卓类药物能力激动剂）和曲唑酮（一种常见的抗抑郁药）在急性（两天）治疗（两周）的治疗（两周），以及这些药物的尖锐性cr刺激性刺激症，以及是否会刺激刺激性刺激性，或者是否会抑制刺激性的刺激性，或者是否会刺激性刺激性，或者是否会抑制刺激性刺激性，或者是否会抑制刺激性刺激性，或者是否会刺激刺激性，或者是否会抑制刺激性，或者是否会抑制刺激性，或者是否会刺激刺激性刺激性，或者是否会抑制刺激性刺激性。通过慢性全身治疗。与对照组相比，所有实验将在新生儿母体剥夺引起的慢性失眠大鼠模型中进行。将应用四种主要技术。这包括（1）对我们的大鼠模型，由新生儿母体剥夺引起的失眠症，（2）多个术记录，一种用于睡眠评估的经典技术，（3）用于细胞外流体收集的微透析和（4）使用doadibemunoMunoAssay来量化CRH和Orexins的水平。我们拥有足够的初步数据，以支持使用这些技术的可行性。临床意义，我们提出了两个目标：回答短期或长期治疗不同类型催眠药的关键问题将恢复睡眠异常和失眠模型中的神经生物学标记。该项目的成功完成将使我们能够概述用埃斯唑啉酮和曲唑酮治疗对睡眠和脑CRH和OREXINS的直接和慢性影响，并将这些药物对下丘脑CRH以及OREXINS的直接作用与失眠治疗的长期功效相关联。这些结果将能够帮助改善慢性失眠的治疗策略的当前理解。拟议工作与VA患者护理任务失眠的相关性是美国普通人群中的一种常见疾病，患有PTSD的人中有70％存在慢性失眠。它导致次日功能障碍和心理困扰受损，并且是后来增加抑郁症风险的预测指标。成功地完成了在失眠症中促促促是对促促是对神经生物学调节的重要新见解的研究研究的研究，并可能为其治疗提供新的方向。 公共卫生相关性： Feng：拟议引起的失眠1的康复1与VA患者护理任务失眠的相关性是美国普通人群中的一种常见疾病，慢性失眠症患有PTSD患者的70％。它导致次日功能障碍和心理困扰受损，并且是后来增加抑郁症风险的预测指标。尽管失眠是PTSD中最常见的睡眠障碍，但医生对其进行经验对待，并且对其相关神经生物学的了解有限。我们对MD大鼠失眠模型的提议评估可能满足对纵向研究，分子研究以及针对唤醒/睡眠调节和失眠的干预措施的有效性和毒性的合格动物模型的需求。我们提出了这个项目的两个目标：回答短期或长期治疗的关键问题，无论是不同类型的催眠药都会恢复睡眠异常和失眠模型中的神经生物学标记。成功完成拟议的研究可能不仅可以证实失眠症中高伴侣的病理调节，而且还为神经生物学调节的失眠症，临床严重程度的新标记以及对直接或辅助治疗的神经途径提供了新的新见解。