PHARMACOLOGICAL STUDIES OF HUMAN AND CANINE NARCOLEPSY

描述(申请人摘要)：这份建议书是一份K01的申请 导师研究科学家发展奖。候选人是一位 神经精神病学家，在神经化学和 神经药理学。应聘者建议获得临床经验 和基础神经药理学。他的目标是开发出更好的药理作用 人类发作性睡病的治疗。人类嗜睡症是一种睡眠障碍 影响总人口的0.05-0.16%。这样做的目的是 建议剖析发作性睡病患者睡眠的神经化学控制 使用药理学方法，并应用这一知识来改善 治疗人类发作性睡病。这不仅对发作性睡病患者有利 但也提供了有关神经化学物质的关键信息 产生正常睡眠的机制。这项研究在很大程度上得益于 一种独特的发作性睡病动物模型的使用 作为一种完全穿透的常染色体隐性遗传性状而传递。在过去 几年来，这位候选人一直专注于药物控制 犬性猝倒，REM睡眠张力的一种病理表现。这个 结果表明，这种症状，如快速眼动睡眠，主要是由 胆碱能和单胺能系统。几种受体亚型 调节这种神经药理控制(毒鼠强M2，肾上腺素能 α-1b和α-2/D2(3))。在本次颁奖期间， 应聘者将：(1)应用肾上腺素系统是 控制猝倒的最重要的单胺能系统获得 用犬模型改进治疗人类猝倒，(2)试验 安非他明类化合物的催醒作用假说 是通过突触前刺激多巴胺能传递介导的 试图将体内对睡眠的影响与体外结合联系起来 多巴胺转运蛋白的亲和力、体外效力 不同药物对多巴胺的摄取抑制及体内效应 促进觉醒的化合物，以及(3)确定 促进清醒的化合物。这将涉及到当地的毒品注射和 活体微透析实验。由于初步结果表明， 发作性睡病与中脑皮质多巴胺能系统的关系 候选人将主要专注于这一解剖系统。结果来自 犬类过度嗜睡的模型也适用于人类。 后期发作性睡病患者。 有了这个研究科学家发展奖，候选人将 为人类的发展或更好的药物治疗做出贡献 嗜睡症，同时也促进了候选人的职业目标，成为 独立科学家。

DESCRIPTION (Applicant's abstract): This proposal is a request for a K01 Mentored Research Scientist Development Award. The candidate is a neuropsychiatrist who is experienced in neurochemistry and neuropharmacology. The candidate proposes to gain experience in clinical and basic neuropharmacology. His goal is to develop better pharmacological treatments for human narcolepsy. Human narcolepsy is a sleep disorder affecting 0.05-0.16% of the general population. The objective of this proposal is to dissect the neurochemical control of sleep in narcolepsy using a pharmacological approach and to apply this knowledge to improve the treatment for human narcolepsy. This will not only benefit narcoleptic patients but also provide critical information on the neurochemical mechanisms generating normal sleep. The research is greatly facilitated by the use of a unique animal model of narcolepsy in which the condition is transmitted as a fully penetrant autosomal recessive trait. In the past several years, the candidate has focused on the pharmacological control of canine cataplexy, a pathological manifestation of REM sleep atonia. The results indicate that this symptom, as REM sleep, is mainly controlled by cholinergic and monoaminergic systems. Several receptor subtypes that mediate this neuropharmacological control (muscarinic M2, adrenergic alpha-lb and alpha-2/D2(3)) have been identified. In this award period, the candidate will: (1) apply the knowledge that the adrenergic system is the most important monoaminergic system for the control of cataplexy obtained using the canine model to improve the treatment of human cataplexy, (2) test the hypothesis that the wake-promoting effects of amphetamine-like compounds are mediated via presynaptic stimulation of the dopaminergic transmission by attempting to correlate the in vivo effects on sleep and in vitro binding affinities for dopamine transporter site, in vitro potencies of dopamine uptake inhibition and in vivo effects on dopamine efflux of various wake-promoting compounds, and (3) determine the sites of action of wake-promoting compounds. This will involve local drug injection and in vivo microdialysis experiments. As preliminary results suggest the involvement of the mesolimbocortical dopaminergic system in narcolepsy, the candidate will principally focus on this anatomical system. Results from the canine model concerning excessive sleepiness could also apply to human narcoleptics at a later stage. With this Research Scientist Development Award, the candidate will contribute to the development or better pharmacological treatments of human narcolepsy while also furthering the candidate's career objective to be an independent scientist.