NEUROCHEMICAL BASIS OF SLEEP HOMEOSTASIS

睡眠稳态的神经化学基础

• 批准号: 6390134
• 负责人: WILLIAM C DEMENT
• 金额: $ 28.67万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-25 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390134
• 关键词: adenosine; behavioral /social science research tag; brain metabolism; dopamine; dopamine antagonists; dopamine receptor; ethology; homeostasis; laboratory rat; methamphetamine; methylphenidate; neural transmission; neurotransmitter transport; oxazolidone; prosencephalon; psychological adaptation; psychopharmacology; sleep; tegmentum

DESCRIPTION (adapted from applicant's abstract): Compensatory sleep responses (CSR) following extended prior waking constitute a central tenet of sleep physiology-- that sleep is "homeostatically" regulated. NonREM sleep time, sleep episode duration, and EEG delta power normally increase proportional to prior wake duration. Waking from stimulants (methamphetamine and methylphenidate) also induce CSR. However, waking induced by pemoline or selective dopamine reuptake blockers (DARBs) produces no CSR, suggesting that dopamine-induced wakefulness can uncouple the sleep homeostatic mechanism. The cholinergic neurons in the nucleus basalis (NBM) and adjacent basal forebrain regions that diffusely project to the cerebral cortex have been extensively characterized in promotion of wakefulness. Because the NBM receives dopaminergic input directly from the ventral tegmental area (VTA), wakefulness produced by DARBs is likely to be mediated directly in this region. Given the hypothetical role of adenosine as an endogenous sleep factor, it is possible that adenosine levels in this region may interact with dopaminergic influences on the NBM. The research proposed investigates dopaminergic interaction with sleep homeostasis in terms of its generality, involvement of the basal forebrain, DA receptor subtypes involved, interaction with sleep deprivation, and interaction with adenosinergic mechanisms that also modulate sleep-wakefulness. Six interrelated specific aims will examine the role of DA in sleep homeostasis using computerized sleep recording, microinjection, and in vivo dialysis techniques in rats. The experiments will test the hypotheses that: 1.) Wakefulness induced by selective increase in DA neurotransmission is uncoupled from the sleep homeostatic process; 2.) Direct VTA dopaminergic projections to the NBM mediate DA waking without subsequent compensatory sleep; 3.) Specific DA receptor subtypes mediate the ability of DARBs to promote waking without subsequent compensatory hypersomnolence; 4.) DA-induced basal forebrain waking counteracts compensatory sleep drive following sleep deprivation; 5.) Elevated adenosine levels mediate hypersomnolence following sleep deprivation or waking induced by classic psychomotor stimulants (methamphetamine, methylphenidate); 6.) Adenosinergic agonists in the NBM can restore CSR after pemoline or DARB-induced wakefulness. Excessive sleepiness undermines the health and quality of life in millions of people including the elderly, sleep apnea sufferers, narcoleptics, and shift-workers. Sleep regulation is also highly disturbed in patients with abnormal DA production, such as in Parkinson's Disease. The proposed studies will advance our basic understanding of central mechanisms underlying compensatory sleep, with the hope that this basic knowledge will lead to better long-term treatments for excessive sleepiness.

描述（改编自申请人的摘要）：补偿性睡眠 延长之前的回复（CSR）构成了中央宗旨 睡眠生理学 - 睡眠受到“体内平衡”的调节。 nonrem 睡眠时间，睡眠发作持续时间和EEG三角洲力量通常会增加 与先前的唤醒持续时间成正比。 从兴奋剂中醒来 （甲基苯丙胺和甲基苯甲酸酯）也诱导CSR。 但是，醒来 由Pemoline或选择性多巴胺再摄取阻滞剂（DARBS）诱导的产生 没有企业社会责任，表明多巴胺引起的觉醒可以使睡眠不合时宜 稳态机制。 底核（NBM）中的胆碱能神经元 和邻近的基础前脑区域，它们扩散地投射到大脑 皮质在促进清醒方面已被广泛特征。 因为NBM直接从腹侧接收多巴胺能输入 细分区域（VTA），DARBS产生的清醒很可能被调节 直接在该区域。 鉴于腺苷作为一种假设的作用 内源性睡眠因子，该区域的腺苷水平可能 可能与多巴胺能对NBM的影响相互作用。 研究提出了 根据其调查多巴胺能与睡眠体内平衡的互动 一般性，基础前脑的参与，DA受体亚型 涉及，与睡眠剥夺的互动以及与 腺苷能的机制也调节睡眠能力。 六 相互关联的特定目的将检查DA在睡眠体内平衡中的作用 使用计算机睡眠记录，显微注射和体内透析 大鼠的技术。 实验将测试以下假设：1。） 选择性增加DA神经传递引起的清醒是 与睡眠体内稳态过程未偶联； 2.）直接VTA多巴胺能 对NBM的预测介导了DA醒来，而无需随后的补偿性 睡觉; 3.）特定的DA受体亚型介导了darbs的能力 促进醒来，而无需随后的补偿性超善； 4.） DA引起的基底前脑醒来反对补偿性睡眠驱动器 睡眠不足； 5.）升高的腺苷水平介导 睡眠不足或经典引起的睡眠剥夺或醒来后的高血压 精神运动刺激剂（甲基苯丙胺，甲基苯甲酸酯）； 6.）腺苷能 NBM中的激动剂可以在Pemoline或Darb诱导后恢复CSR 清醒。 过度嗜睡会破坏健康和生活质量 在包括老年人，睡眠呼吸暂停患者在内的数百万人中， 麻醉剂和转换工人。 睡眠调节也受到高度干扰 DA产生异常的患者，例如帕金森氏病。 拟议的研究将提高我们对中央的基本理解 补偿性睡眠的基础机制，希望这种基本 知识将导致更好的长期治疗，以使过度嗜睡。