NEUROTRANSMITTER MECHANISMS IN CANINE NARCOLEPSY

这个项目的目标是确定单胺、乙酰胆碱 和其他神经递质在中枢神经系统相互作用 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，而猝倒和 睡眠模式被记录下来。神经递质的释放也被测量 在猝倒期间(活体透析)在相同的区域。 在过去的获奖期内，我们发现在 基底前脑(BF)和桥脑网状结构(PRF) 对毒扁豆碱刺激过敏，这一过程 会导致猝倒症。乙酰胆碱的释放也增加了 自发性猝倒时这两个区域都显示胆碱能 在此行为期间，系统处于活动状态。我们现在假设 情绪刺激导致BF中乙酰胆碱的释放。 由于这种过敏性，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)会产生嗜睡和 发作性睡病犬的猝倒。由于VTA是 从BF向下的投影，我们假设相互作用 VTA和BF之间的关系导致白天过多 嗜睡症引起的嗜睡。 在接下来的颁奖期间，我们将对这些假设进行决定性的检验 使用相同的方法。我们还将进一步 表征肾上腺素能系统的参与，因为我们的结果是 数据令人惊讶地表明，肾上腺素能的作用部位 猝倒时的化合物可能不涉及蓝斑。 霍乱毒素免疫细胞化学技术及图谱研究 胆碱能和单胺能神经系统的研究也将完成 以确定神经解剖学上的联系。 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。

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.