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.

睡眠障碍是影响北美0.05-0.10％的睡眠障碍 人口。我们的目标是剖析睡眠的神经化学控制 使用药理学方法中的发肠病疗，并应用此知识 为了改善人类麻醉症的治疗。这也将提供 有关神经化学机制产生正常机制的关键信息 睡觉。使用的犬模型可以促进我们的研究 发肠病中该病情被传播为完全渗透物 常染色体隐性特征。该提议是一个竞争性的续约 RO1赠款最初于1989年资助。 我们专注于犬曲线的药理控制， REM Sleep Atonia的病理表现，也是最多的 残障人性疾病的症状。我们的结果表明这 类似于REM睡眠的症状主要由胆碱能控制和 单胺能系统。我们已经确定了几个受体 介导这种神经药物控制的亚型：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 麻醉和对照动物之间的中间表型。三分之二 杂合犬的狗，但从未有任何控制犬 在胆碱能特定的药理条件下的攻击 刺激传播并降低单胺能传播。 使用麻醉剂，杂合和对照进行睡眠记录实验 杜伯曼人还证明了麻醉犬显着 在白天比对照更睡觉，少数杂合动物 测试是中介。 在下一阶段的资金阶段，我们将：（1）应用获得的知识 从我们在犬类上的药理学实验来改善治疗 人类瘫痪； （2）进一步表征纯合的表型 麻醉和杂合载体Dobermans。 （3）检验假设 通过 多巴胺能传播的突触前刺激。测试这个 假设，我们将尝试将体内对睡眠的影响相关联 多巴胺转运蛋白部位和体外的体外结合亲和力 多巴胺摄取抑制剂的各种兴奋剂的效力。 （4）确定 刺激化合物作用以引起警觉性。这将涉及本地 药物注射和体内微透析实验。作为我们的初步 结果表明中唇或皮层多巴胺能参与 发作性的系统，我们将主要专注于这些神经解剖学 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，组敏能，腺苷能， 苯二氮卓能和α-1化合物）。 该建议将增强我们对 发肠病和刺激化合物的作用方式。它应该 还为开发非添加性兴奋剂的开发提供了新的方向 具有较高功效的化合物。