NEUROPHARMACOLOGY OF HUMAN AND CANINE NARCOLEPSY

人类和犬类发作性睡病的神经药理学

• 批准号: 2519930
• 负责人: Emmanuel J Mignot
• 金额: $ 27.06万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2519930
• 关键词: adenosine; amphetamines; benzodiazepines; cataplexy; central nervous system stimulants; dogs; dopamine; dopamine transporter; drug interactions; electroencephalography; heterozygote; histamine; homozygote; human subject; human therapy evaluation; microdialysis; narcolepsy; nervous system disorder chemotherapy; neuropharmacology; neurotransmitter transport; nonhuman therapy evaluation; norepinephrine; polygraphy; synaptosomes; thyrotropin releasing hormone

Narcolepsy is a sleep disorder affecting 0.05-0.10% of the North American population. Our objective is to dissect the neurochemical control of sleep in narcolepsy using a pharmacological approach and to apply this knowledge to improve the treatment of human narcolepsy.This will also provide critical information on the neurochemical mechanisms generating normal sleep. Our research is facilitated by the use of a canine model of narcolepsy in which the condition is transmitted as a fully penetrant autosomal recessive trait. This proposal is a competitive renewal of an RO1 grant that was originally funded in 1989. We have focused on the pharmacological control of canine cataplexy, a pathological manifestation of REM sleep atonia, and one of the most disabling symptoms of human narcolepsy. Our results indicate that this symptom, similar to REM sleep, is mainly controlled by cholinergic and monoaminergic systems. We have farther identified several receptor subtypes that mediate this neuropharmacological control: muscarinic M2, adrenergic alpha-1b and alpha-2/D2 receptor subtypes. Preliminary experiments also suggest that heterozygous animals have an intermediary phenotype between narcoleptic and control animals. Two-thirds of heterozygous dogs, but never any control dogs, display cataplectic attacks under specific pharmacological conditions where cholinergic transmission is stimulated and monoaminergic transmission is depressed. Sleep recording experiments using narcoleptic, heterozygous and control Dobermans have also demonstrated that narcoleptic dogs are significantly sleepier than controls during the daytime, the few heterozygous animals tested being intermediary. In the next period of funding, we will: (1) apply the knowledge obtained from our pharmacological experiments on canines to improve the treatment of human cataplexy; (2) further characterize the phenotype of homozygous narcoleptic and heterozygous carrier Dobermans. (3) test the hypothesis that the alerting effects of amphetamine-like stimulants are mediated via presynaptic stimulation of dopaminergic transmission. To test this hypothesis, we will attempt to correlate in vivo effects on sleep, in vitro binding affinities for dopamine transporter sites and in vitro dopamine uptake inhibition potency of various stimulants. (4) determine where stimulant compounds act to induce alertness. This will involve local drug injection and in vivo microdialysis experiments. As our preliminary results suggest the involvement of mesolimbic or mesocortical dopaminergic systems in narcolepsy, we will principally focus on these neuroanatomical systems. (5) study the mode of action and the efficacy of other less known classes of stimulants (TRH, histaminergic, adenosinergic, benzodiazepinergic, and alpha-1 compounds). This proposal will enhance our understanding of the pathophysiology of narcolepsy and of the mode of action of stimulant compounds. It should also provide new directions for the development of non-addictive stimulant compounds with higher efficacy.

发作性睡病是一种睡眠障碍，影响着 0.05-0.10% 的北美人 人口。我们的目标是剖析睡眠的神经化学控制 使用药理学方法治疗发作性睡病并应用这些知识 改善人类发作性睡病的治疗。这也将提供 关于产生正常神经化学机制的关键信息 睡觉。我们的研究是通过使用犬科动物模型来促进的 发作性睡病，其中病症以完全渗透性的形式传播 常染色体隐性遗传特征。该提案是一项竞争性更新 RO1 赠款最初于 1989 年资助。 我们专注于犬猝倒症的药物控制，这是一种 快速眼动睡眠乏力的病理表现，也是最常见的症状之一 人类发作性睡病的致残症状。我们的结果表明这 与快速眼动睡眠类似的症状，主要受胆碱能和 单胺能系统。我们进一步鉴定了几种受体 介导这种神经药理学控制的亚型：毒蕈碱 M2， 肾上腺素能 α-1b 和 α-2/D2 受体亚型。 初步实验还表明，杂合动物具有 发作性睡病动物和对照动物之间的中间表型。三分之二 的杂合狗（但没有任何对照狗）表现出瘫痪 在胆碱能的特定药理条件下发生攻击 刺激传输并抑制单胺能传输。 使用发作性睡病、杂合子和对照进行睡眠记录实验 杜宾犬还证明，患有嗜睡症的狗显着 少数杂合动物在白天比对照组更困 经测试是中介。 在下一期的资助中，我们将：（1）应用所获得的知识 通过我们对犬类的药理学实验来改善治疗 人类猝倒症； (2) 进一步表征纯合子的表型 发作性睡病和杂合携带者杜宾犬。 (3)检验假设 安非他明类兴奋剂的警觉作用是通过 多巴胺能传递的突触前刺激。为了测试这个 假设，我们将尝试将体内对睡眠的影响关联起来， 多巴胺转运蛋白位点的体外结合亲和力和体外 各种兴奋剂的多巴胺摄取抑制效力。 (4)确定 兴奋剂化合物起到引起警觉性的作用。这将涉及本地 药物注射和体内微透析实验。作为我们初步的 结果表明中脑边缘或中皮质多巴胺能的参与 发作性睡病的系统，我们将主要关注这些神经解剖学 系统。 (5)研究其他鲜为人知的作用方式和功效 兴奋剂类别（TRH、组胺能、腺苷能、 苯二氮卓类化合物和 α-1 化合物）。 该建议将增强我们对病理生理学的理解 发作性睡病和兴奋剂化合物的作用方式。它应该 也为非成瘾性兴奋剂的开发提供了新的方向 功效更高的化合物。