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Journal of Neuroscience, Vol 15, 4806-4814, Copyright © 1995 by Society for Neuroscience
Muscle atonia is triggered by cholinergic stimulation of the basal forebrain: implication for the pathophysiology of canine narcolepsy
S Nishino, M Tafti, MS Reid, J Shelton, JM Siegel, WC Dement and E Mignot
Stanford University, Stanford Sleep Disorders Research Center, Palo Alto, California 94304, USA.
Narcolepsy is a sleep disorder characterized by excessive daytime
sleepiness and rapid eye movement (REM) sleep-related symptoms, such as
cataplexy. The exact pathophysiology underlying the disease is unknown but
may involve central cholinergic systems. It is known that the brainstem
cholinergic system is activated during REM sleep. Furthermore, REM sleep
and REM sleep atonia similar to cataplexy can be triggered in normal and
narcoleptic dogs by stimulating cholinergic receptors within the pontine
brainstem. The pontine cholinergic system is, therefore, likely to play a
role in triggering cataplexy and other REM-related abnormalities seen in
narcolepsy. The other cholinergic system that could be involved in the
pathophysiology of narcolepsy is located in the basal forebrain (BF). This
system sends projections to the entire cerebral cortex. Since acetylcholine
release in the cortex is increased both during REM and wake, the
basocortical cholinergic system is believed to be involved in cortical
desynchrony. In the current study, we analyzed the effect of cholinergic
compounds injected into the forebrain structures of narcoleptic and control
dogs. We found that carbachol (a cholinergic agonist) injected into the BF
triggers cataplexy in narcoleptic dogs while it increases wakefulness in
control dogs. Much higher doses of carbachol bilaterally injected in the BF
were, however, shown to trigger muscle atonia even in control dogs. These
results suggest that a cholinoceptive site in the BF is critically
implicated in triggering muscle atonia and cataplexy. Together with similar
results previously obtained in the pontine brainstem, it appears that a
widespread hypersensitivity to cholinergic stimulation may be central to
the pathophysiology of canine narcolepsy.(ABSTRACT TRUNCATED AT 250 WORDS)
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