NEUROPHARMACOLOGY OF AROUSAL AND SLEEP DISORDERS

描述（由申请人提供）：本研究计划的主要目的是研究觉醒和睡眠的神经药理学细胞机制，特别强调发作性睡病的发病机制。下丘脑分泌素/食欲素，新发现的肽神经递质及其受体将进行研究。下丘脑分泌素/食欲素及其受体在嗜睡症和睡眠障碍以及食物摄入调节中发挥作用。目前对它们对大脑神经元的生理影响知之甚少。先前的研究表明，下丘脑分泌素/食欲素通过脑核中的下丘脑分泌素2/食欲素2受体产生的兴奋缺乏是发作性睡病的核心成分。拟议的项目重点是通过分离大鼠和小鼠参与调节觉醒和睡眠的脑核的原代培养，进一步阐明它们在细胞和分子水平上的作用。具体项目有：(1)阐明下丘脑泌素/食欲素对富含下丘脑泌素2/食欲素2受体的结节乳头核组胺能神经元的影响；(2)确定递质对富含下丘脑泌素1/食欲素1受体的蓝斑去甲肾上腺素能神经元的影响；(3)研究下丘脑泌素/食欲素对Meynert基底核胆碱能神经元的影响。此外，一个异源系统（HEK293A）

DESCRIPTION (provided by applicant): The main objective of this research proposal is to investigate neuropharmacologically the cellular mechanisms of arousal and sleep with a special emphasis on the pathogenesis of narcolepsy. Hypocretins/orexins, newly discovered peptide neurotransmitters, and their receptors will be studied. Hypocretins/orexins and their receptors play a role in narcolepsy and sleep disorders and in the regulations of food intake. Currently little is known about their physiological effects on brain neurons. Previous studies have shown that lack of excitation produced by hypocretins/orexins through hypocretin2/orexin2 receptors in the brain nuclei is the central component of narcolepsy. Proposed projects focus on further elucidating their actions at the cellular and molecular level by using dissociated primary cultures of rat and mouse brain nuclei that are involved in regulating arousal and sleep. The specific projects are: (1) to elucidate hypocretin/orexin effects on histaminergic neurons in the tuberomammillary nucleus which are rich in hypocretin2/orexin2 receptors, (2) to determine the transmitter effects on noradrenergic neurons in the locus coeruleus which are rich in hypocretin1/orexin 1 receptors, and (3) to investigate hypocretin/orexin effects on cholinergic neurons in the nucleus basalis of Meynert. In addition, a heterologous system (HEK293A) which is transfected with each type of hypocretin/orexin receptor will be used. All of these projects emphasize elucidating signal transduction mechanisms of hypocretins/orexins, and determining the identity and roles of G proteins. Electrophysiological techniques (patchclamp) and pharmacological techniques combined with molecular biological methods will be used. These projects are important for deepening the understanding of narcolepsy and other sleep disorders. The knowledge obtained is essential in developing more effective treatments for narcolepsy and other sleep disorders. This research on the sleep-arousal centers of the brain will contribute in helping those who suffer sleep disorders.