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Involvement of central noradrenergic and cholinergic mechanisms in control of cataplexy in canine narcolepsy. Seiji NISHINO 1,2 , Emmanuel Mignot 2 , Kenji KURODA 1 , Toshiaki SAKAI 1 , William C. Dement 2 1Department of Neuropsychiatry, Osaka Medical College 2Stanford University Sleep Disorders Center pp.461-473
Published Date 1990/6/10
DOI https://doi.org/10.11477/mf.1431900046
  • Abstract
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Canine narcolepsy is a genetically transmitted animal model of human narcolepsy, a disorder of rapid eye movement (REM) sleep characterized by excessive daytime sleepiness and cataplexy (dramatic episodes of muscle weakness induced by emotions). The elucidation of the mechanisms involved in cataplexy is very closely linked to the understanding of REM sleep and the muscle atonia normally present during this sleep stage. Narcoleptic dogs have been extensively used in vivo and in vitro to investigate the pathophysiology of narcolepsy and to elaborate new therapeutic strategies for human narcolepsy.

The importance of pontine cholinergic systems in REM sleep regulation has been well established by both in vivo pharmacology and experiments involving the local stimulation of selective brainstem regions. In canine narcolepsy, central muscarinic stimulation with physostigmine increases cataplexy, while cholinergic blockade with atropine improves cataplexy. This pharmacological result suggests that a central cholinergic mechanism is involved in the control of cataplexy in canine narcolepsy. In addition to the cholinergic mechanisms, central monoaminergic mechanisms have been thought to be involved in REM sleepregulation and narcolepsy. Antidepressant drugs (monoamine uptake blockers) and amphetamine-like compounds (monoamine releasing agents) are treatments of choice for human narcolepsy and are also very potent at reducing canine cataplexy. However, these two classes of drugs are pharmacologically very non-specific, and globally act to increase monoamine levels (norepinephrine, dopamine, and serotonin) in the synaptic cleft. These global pharmacological effects on monoaminergic mechanisms needed to be more specifically investigated by using drugs selective for a single monoamine and, if possible, for individual postsynaptic receptors. We therefore explored the effect on canine cataplexy of various compounds selective for the noradrenergic, dopaminergic, or serotonergic systems. Results to date clearly demonstrate a preferential involvement of norepinephrine over dopamine or serotonin. The most potent compounds reducing canine cataplexy are the noradrenergic uptake blockers (such as nisoxetine), the alpha-1 agonists (such as methoxamine) or the alpha-2 antagonists (such as yohimbine), whereas the alpha-1 antagonists (such as prazosin) and some alpha-2 agonists (such as BHT-920) are extremely potent cataplexy-inducing compounds. Alpha-2 receptors are known to be located pre- and post-synaptically and it is difficult to infer if either or both site(s) are implicated in the observed effect above. We, however, favor the interpretation that the effects of alpha-2 compounds on cataplexy are mediated through presynaptic alpha-2 receptors (which are involved in the autoinhibition of norepinephrine release) since alpha-2 blockade mimics the effects of alpha-1 stimulation (arousal and decrease in cataplexy), whereas alpha-2 stimulation with BHT-920 reproduces the effect of alpha-1 antagonists (decrease in arousal and increase in cataplexy) in the canine model. These results all suggest that noradrenergic mechanisms are inhibitory to REM sleep and cataplexy, and that the final common pathway involves a postsynaptic alpha-1 receptor. Based on this pharmacological evidence, studies of alpha adrenoceptor levels and affinities in various brain areas of narcoleptic and control dogs were conducted. The most notable findings of these receptor studies were a selective increase in alpha-1 adrenergic receptors in the amygdala and an increase of alpha-2 receptors in the locus coeruleus" in narcoleptic dogs, compared to breed and age matched controls.


Copyright © 1990, Igaku-Shoin Ltd. All rights reserved.

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電子版ISSN 1882-1243 印刷版ISSN 0001-8724 医学書院

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