Neuropharmacology and neurochemistry of canine narcolepsy.
Neuropharmacology and neurochemistry of canine narcolepsy.
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DOI：
10.1093/sleep/17.suppl_8.s84
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发表时间：
1994-12
期刊：
影响因子：
5.6
通讯作者：
S. Nishino;M. Reid;W. Dement;E. Mignot
中科院分区：
文献类型：
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作者：
S. Nishino;M. Reid;W. Dement;E. Mignot
据信，发作性睡病涉及快速眼动（REM）睡眠异常，尤其是快速眼动睡眠缺乏张力。令人信服的证据表明，快速眼动睡眠和快速眼动睡眠张力缺乏的调节涉及胆碱能系统和单胺能系统的相互作用。使用我们的犬类发作性睡病模型和药理学方法，我们之前已经证明了猝倒调节中类似的相互作用。胆碱能或单胺能传递的整体激活分别加重或抑制犬类猝倒。我们还鉴定了专门参与这种相互作用的单胺能受体和胆碱能受体的亚型。通过 M2 刺激激活胆碱能系统，以及通过阻断突触后 α-1b 受体或刺激 α-2 或 D2 抑制性自身受体使儿茶酚胺能系统失活，会加剧猝倒。这些药理学结果与先前发现的犬发作性睡病的神经化学异常相对应，例如与对照动物相比，脑桥中的 M2 受体、杏仁核中的 α-1 受体、蓝斑中的 α-2 受体以及杏仁核和伏核中的 D2 受体显着增加。通过局部灌注活性化合物，我们进一步证明桥脑网状结构以及基底前脑中的胆碱感受位点参与猝倒的调节。尽管单胺能化合物的具体作用位点仍然未知，但我们迄今为止的药理学和神经化学研究结果表明，中枢神经系统内胆碱能系统的广泛过度活跃以及儿茶酚胺能系统的低活性是发作性睡病的病理生理学基础。
It is believed that narcolepsy involves abnormalities of rapid eye movement (REM) sleep, especially of REM sleep atonia. Compelling evidence suggests that the regulation of REM sleep and REM sleep atonia involves a reciprocal interaction of cholinergic and monoaminergic systems. Using our canine model of narcolepsy and a pharmacological approach, we have previously demonstrated a similar interaction in the regulation of cataplexy. Global activation of cholinergic or monoaminergic transmission aggravates or suppresses canine cataplexy, respectively. We have also identified the subtypes of monoaminergic and cholinergic receptors specifically involved in this interaction. Cataplexy is aggravated by activation of the cholinergic system via M2 stimulation, as well as deactivation of the catecholaminergic systems by either blockade of postsynaptic alpha-1b receptors or stimulation of alpha-2 or D2 inhibitory autoreceptors. These pharmacological results correspond to previously identified neurochemical abnormalities in canine narcolepsy, such as significant increases in M2 receptors in the pons, alpha-1 receptors in the amygdala, alpha-2 receptors in the locus coeruleus and D2 receptors in the amygdala and nucleus accumbens, when compared to control animals. Using local perfusion of active compounds, we have further demonstrated that cholinoceptive sites in the pontine reticular formation, as well as in the basal forebrain, are involved in the regulation of cataplexy. Although the specific sites of action of the monoaminergic compounds remain unknown, the results of our pharmacological and neurochemical studies to date suggest that a widespread hyperactivity of cholinergic systems within the central nervous system together with a hypoactivity of catecholaminergic systems underlie the pathophysiology of narcolepsy.