NEUROTRANSMITTER MECHANISMS IN CANINE NARCOLEPSY

犬嗜睡症的神经递质机制

• 批准号: 6273747
• 负责人: SEIJI NISHINO
• 金额: $ 22.27万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6273747
• 关键词: REM sleep; acetylcholine; amine oxidase (flavin); cataplexy; choline; disease /disorder model; dogs; electroencephalography; electromyography; electrooculography; electrophysiology; high performance liquid chromatography; immunocytochemistry; narcolepsy; neurotransmitters; perfusion; sleep

The goal of this project is to determine how monoamines, acetylcholine and other neurotransmitters interact in the central nervous system to regulate cataplexy and sleepiness in narcolepsy. Pharmacological compounds are injected into specific brain areas while cataplexy and sleep patterns are recorded. Neurotransmitter release is also measured in the same areas during cataplexy (in vivo dialysis). In the past award period, we have found that cholinoceptive sites within the basal forebrain (BF) and the pontine reticular formation (PRF) are hypersensitive to muscarinic stimulation and that this process contributes to cataplexy. Acetylcholine release is also increased in both areas during spontaneous cataplexy demonstrating that cholinergic systems are active during this behavior. We now hypothesize that emotional stimulation results in acetylcholine release in the BF. Because of the hypersensitivity, we hypothesize that this induces widespread cholinergic activation and REM sleep-like symptoms. A second important finding is that dopaminergic D2/D3 autoreceptor stimulation in the ventral tegmental area (VTA) produced sleepiness and cataplexy in narcoleptic dogs. Since the VTA is a major site of descending projections from the BF, we hypothesize that interactions between the VTA and the BF contribute to the excessive daytime sleepiness experienced by narcolepsy. In the next award period, we will conclusively test these hypotheses using the same methodological approach. We will also further characterize the involvement of adrenergic systems as our results to date surprisingly suggest that the site of action of adrenergic compounds on cataplexy may not involve the locus coeruleus. Immunocytochemical techniques using cholera toxin and mapping studies of the cholinergic and monoaminergic neuronal systems will also be done to identify neuroanatomical connections. Using these approaches, we will establish a neurochemical and neuroanatomical map of the structures and neurotransmitters that control rapid eye movement (REM) sleep and produce the abnormal manifestations of narcolepsy.

该项目的目的是确定单胺，乙酰胆碱如何 和其他神经递质在中枢神经系统中相互作用 调节发作性疾病的瘫痪和嗜睡。药理 静脉曲张和 记录睡眠方式。还测量了神经递质释放 在催化过程中的同一区域（体内透析）。 在过去的奖项期间，我们发现内部的胆碱感位 基础前脑（BF）和蓬丁网状形成（PRF）是 对毒蕈碱刺激的高度敏感，这一过程 有助于脱失。乙酰胆碱释放也增加了 自发性脱囊中的两个区域都证明了胆碱能 在这种行为中，系统是活跃的。我们现在假设 情绪刺激导致BF中的乙酰胆碱释放。 由于过敏，我们假设这会引起 广泛的胆碱能激活和类似REM睡眠状症状。 第二个重要发现是多巴胺能D2/D3自身受体 腹侧对接区域（VTA）刺激产生嗜睡和 麻醉犬中的脱囊。由于VTA是 我们从BF降临预测，我们假设相互作用 VTA和BF之间有助于白天过多 嗜睡是由睡病经历的。 在下一个奖项期间，我们将最终检验这些假设 使用相同的方法论方法。我们还将进一步 表征肾上腺素能系统的参与为我们的结果 日期令人惊讶地表明肾上腺素能的作用部位 脱囊上的化合物可能不涉及基因座凝固。 使用霍乱毒素和作图研究的免疫细胞化学技术 还将完成胆碱能和单胺能神经元系统的 识别神经解剖学连接。 使用这些方法，我们将建立一个神经化学和 控制结构和神经递质的神经解剖图 快速眼动（REM）睡眠并产生异常表现 发作性蠕虫。