Neuropharmacology and neurochemistry of canine narcolepsy.
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.
Nishino
S
S
Sleep Research Center, Stanford University School of Medicine, Palo Alto, California.
Reid
M S
MS
Dement
W C
WC
Mignot
E
E
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced; D004285:Dogs; D009290:Narcolepsy; D018377:Neurotransmitter Agents; D017983:Receptors, Catecholamine; D011950:Receptors, Cholinergic / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects; D012895:Sleep, REM
D018377:Neurotransmitter Agents; D017983:Receptors, Catecholamine; D011950:Receptors, Cholinergic; D011976:Receptors, Muscarinic; D002217:Carbachol; D000109:Acetylcholine