NEUROPHARMACOLOGY OF HUMAN NARCOLEPSY

人类嗜睡症的神经药理学

• 批准号: 2266558
• 负责人: WILLIAM C DEMENT
• 金额: $ 35万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2266558
• 关键词: REM sleep; adrenergic agents; adrenergic receptor; alpha adrenergic agent; alpha antiadrenergic agent; amines; cataplexy; cholinergic agents; cholinergic receptors; disease /disorder model; dogs; dopamine; electroencephalography; electromyography; electrooculography; fluoxetine; gene expression; human subject; immunocytochemistry; in situ hybridization; narcolepsy; neuroanatomy; neurochemistry; neuropharmacology; oncogenes

Human narcolepsy is a disabling disorder of sleep and wakefulness that affects 0.1% of the general population. The singular objective of this project is to dissect the neurochemical control of normal and pathological sleep processes using a pharmacological approach and to utilize this new knowledge in the development of new treatments for human narcolepsy. Understanding narcolepsy should not only help narcoleptic patients but also provide critical information on the neurochemical mechanisms that generate normal sleep, with possible applications that extend to other areas of sleep medicine. Research is greatly facilitated by the use of an animal model of the human disorder (autosomal recessive narcolepsy) which is independently funded for an additional two years. This project is a competitive renewal of an R01 grant that has been funded for three years. In the past funding period, we have demonstrated that cataplexy, a pathological model of REM sleep atonia, is mainly controlled by two neurochemical systems, the cholinergic and the noradrenergic systems. We have also identified a number of receptor subtypes that mediate these neurochemical effects: muscarinic M2, alpha-lb adrenergic, and D2/alpha-2 receptor subtypes. In the next period of funding, we will (1) further our identification of monoaminergic and cholinergic receptor subtypes involved in the control of cataplexy and REM sleep atonia. Coadministration studies of compounds acting on monoaminergic and cholinergic systems will also be performed to examine how these systems interact synergistically. (2) Assess the role of key non-cholinergic, non-monoaminergic systems by studying the effects of intracerebroventricular infusion of candidate peptides. (3) Characterize compound effects on sleep and wakefulness in narcoleptic canines using electroencephalographic (EEG) recording techniques. One compound from each pharmacological class that modified cataplexy in our previous studies will be explored. This will include studying the effects of these compounds on sleep-wake patterns, EEG spectral analysis, and alertness using a canine version of the Multiple Sleep Latency Test. (4) Determine the site of action of pharmacologically active compounds by local pharmacological injections and studies of immediate early gene expression. (5) Use antidepressant compounds that selectively block monoamine uptake to investigate the hypothesis that the effect of current treatments of narcoleptic patients is mediated via an activation of noradrenergic systems.

人类发作性睡病是一种睡眠和觉醒的致残性疾病， 影响总人口的0.1%。 此次活动的唯一目的 项目的目的是剖析正常和正常的神经化学控制 使用药理学方法研究病理性睡眠过程 利用这些新知识开发人类新疗法 发作性睡病。 了解发作性睡病不仅应该帮助发作性睡病患者 患者还提供有关神经化学物质的关键信息 产生正常睡眠的机制，以及可能的应用 扩展到睡眠医学的其他领域。 极大地方便了研究 通过使用人类疾病（常染色体隐性遗传）的动物模型 发作性睡病），额外独立资助两年。 该项目是 R01 赠款的竞争性更新，该赠款已 资助三年。 在过去的资助期间，我们已经证明了猝倒症是一种 REM睡眠乏力的病理模型，主要受两个因素控制 神经化学系统、胆碱能系统和去甲肾上腺素能系统。 我们 还确定了许多介导这些的受体亚型 神经化学作用：毒蕈碱 M2、α-1b 肾上腺素能和 D2/α-2 受体亚型。 在下一期的资助中，我们将（1）进一步 我们对单胺能和胆碱能受体亚型的鉴定 参与猝倒和快速眼动睡眠乏力的控制。 作用于单胺能和单胺能的化合物的共同给药研究 胆碱能系统也将被执行以检查这些系统如何 相互作用协同。 (2) 评估关键非胆碱能的作用， 通过研究非单胺能系统的影响 候选肽的脑室内输注。 (3) 表征 使用对发作性睡病犬的睡眠和觉醒的复合影响 脑电图（EEG）记录技术。 一种化合物来自 我们之前的每一种改变猝倒的药理学类别 将进行研究探讨。 这将包括研究以下因素的影响： 这些化合物对睡眠-觉醒模式、脑电图频谱分析和 使用犬类版本的多次睡眠潜伏期测试来提高警觉性。 (4) 通过以下方式确定药理活性化合物的作用位点 局部药物注射及即早基因研究 表达。 (5) 使用选择性阻断的抗抑郁化合物 单胺摄取来研究电流的影响的假设 发作性睡病患者的治疗是通过激活 去甲肾上腺素能系统。