NEUROTRANSMITTER MECHANISMS IN CANINE NARCOLEPSY

犬嗜睡症的神经递质机制

• 批准号: 6296926
• 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/6296926
• 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.

该项目的目标是确定单胺、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 调节发作性睡病的猝倒和嗜睡。药理作用 化合物被注射到特定的大脑区域，同时猝倒和 睡眠模式被记录。还测量神经递质释放 在猝倒（体内透析）期间的相同区域。 在过去的奖励期间，我们发现胆碱感受位点 基底前脑 (BF) 和桥脑网状结构 (PRF) 是 对毒蕈碱刺激过敏并且这个过程 导致猝倒。乙酰胆碱的释放也增加 自发性猝倒期间的两个区域都表明胆碱能 在此行为期间系统处于活动状态。我们现在假设 情绪刺激会导致 BF 中乙酰胆碱的释放。 由于超敏反应，我们假设这会导致 广泛的胆碱能激活和快速眼动睡眠样症状。 第二个重要发现是多巴胺能 D2/D3 自身受体 刺激腹侧被盖区（VTA）会产生困倦感 发作性睡病犬的猝倒。由于 VTA 是 从 BF 的下降预测，我们假设相互作用 VTA 和 BF 之间导致白天时间过长 嗜睡症所经历的嗜睡。 在下一个奖励期，我们将最终检验这些假设 使用相同的方法论。我们还将进一步 将肾上腺素能系统的参与描述为我们的结果 日期令人惊讶地表明肾上腺素的作用位点 关于猝倒的化合物可能不涉及蓝斑。 使用霍乱毒素的免疫细胞化学技术和图谱研究 胆碱能和单胺能神经系统的研究也将完成 识别神经解剖学联系。 使用这些方法，我们将建立一种神经化学和 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 发作性睡病。