Muscle atonia is triggered by cholinergic stimulation of the basal forebrain: implication for the pathophysiology of canine narcolepsy.
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)
Nishino
S
S
Stanford University, Stanford Sleep Disorders Research Center, Palo Alto, California 94304, USA.
Tafti
M
M
Reid
M S
MS
Shelton
J
J
Siegel
J M
JM
Dement
W C
WC
Mignot
E
E
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002385:Cataplexy / Q000503:physiopathology; D018678:Cholinergic Agents / Q000494:pharmacology*; D004285:Dogs; D004569:Electroencephalography; D005260:Female; D008297:Male; D009129:Muscle Tonus / Q000187:drug effects; D009135:Muscular Diseases / Q000139:chemically induced* / Q000503:physiopathology; D009290:Narcolepsy / Q000503:physiopathology*; D016548:Prosencephalon / Q000187:drug effects* / Q000503:physiopathology
D018678:Cholinergic Agents; D002217:Carbachol