PHARMACOLOGICAL STUDIES OF HUMAN AND CANINE NARCOLEPSY

描述（申请人摘要）：本提案是对K 01的请求 科学家发展奖。 候选人是 在神经化学方面经验丰富的神经精神病学家， 神经药理学 候选人建议获得临床经验 和基本的神经药理学 他的目标是开发更好的药理学 人类嗜睡症的治疗方法 人类嗜睡症是一种睡眠障碍 影响总人口的0.05-0.16%。 的目的 一项研究计划是剖析嗜睡症患者睡眠的神经化学控制 使用药理学方法，并应用这些知识来改善 治疗人类嗜睡症 这不仅有利于嗜睡症患者 病人，而且还提供了关于神经化学物质的关键信息， 产生正常睡眠的机制 这项研究得到了极大的促进， 使用一种独特的发作性睡病动物模型， 作为一种完全外显的常染色体隐性遗传性状传递。 过去 几年来，候选人一直专注于药理学控制， 犬紧张症，一种快速眼动睡眠张力缺乏的病理表现。 的 结果表明，这种症状，作为快速眼动睡眠，主要是由 胆碱能和单胺能系统。 几种受体亚型， 介导这种神经药理学控制（毒蕈碱M2，肾上腺素能 α-Ib和α-2/D2（3））。 在此期间， 候选人将：（1）应用肾上腺素能系统是 最重要的单胺能系统的控制cataesthetics获得 使用犬模型来改善人类癫痫的治疗，（2）测试 安非他明类化合物的促醒作用假说 是通过多巴胺能传递的突触前刺激介导的 试图将体内对睡眠的影响与体外结合 多巴胺转运蛋白位点亲和力，多巴胺体外效力 摄取抑制和对多巴胺流出的体内影响 唤醒促进化合物，和（3）确定的作用部位 促进清醒的化合物 这将涉及当地药物注射和 体内微透析实验。 初步结果显示， 发作性睡病中脑边缘皮质多巴胺能系统的参与， 候选人将主要集中在这个解剖系统。 结果 关于过度嗜睡犬模型也可以应用于人 发作性睡病患者 凭借这一研究科学家发展奖，候选人将 有助于开发或更好地药理学治疗人类 嗜睡症，同时也促进了候选人的职业目标，成为一个 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.