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神经系统，觉醒和睡眠的细胞机制，特别强调发作性睡病的发病机制。将研究新发现的肽类神经递质Hypocretins/orexins及其受体。下丘脑泌素/食欲素及其受体在嗜睡症和睡眠障碍以及食物摄入的调节中发挥作用。目前人们对它们对大脑神经元的生理影响知之甚少。以往的研究表明，缺乏由hypocretins/orexins通过脑核团中的hypocretin 2/orexin 2受体产生的兴奋是嗜睡症的中心组成部分。拟议的项目集中在进一步阐明他们的行动，在细胞和分子水平上，通过使用大鼠和小鼠脑细胞核，参与调节觉醒和睡眠的解离原代培养物。具体项目有：（1）阐明下丘脑泌素/食欲素对结节乳头核中富含下丘脑泌素2/食欲素2受体的组胺能神经元的作用，（2）确定递质对蓝斑中富含下丘脑泌素1/食欲素1受体的去甲肾上腺素能神经元的作用，（3）研究下丘脑泌素/食欲素对Meynert基底核中胆碱能神经元的作用。此外，异源系统（HEK 293 A） 其用每种类型的下丘脑分泌素/食欲素受体转染。这些项目都强调阐明hypocretins/orexins的信号转导机制，并确定G蛋白的身份和作用。将使用电生理技术（膜片钳）和药理学技术结合分子生物学方法。这些项目对于加深对嗜睡症和其他睡眠障碍的理解非常重要。所获得的知识对于开发更有效的治疗嗜睡症和其他睡眠障碍至关重要。这项关于大脑睡眠唤醒中心的研究将有助于帮助那些患有睡眠障碍的人。

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.