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Effects of central alpha-2 adrenergic compounds on canine narcolepsy, a disorder of rapid eye movement sleep

S Nishino, L Haak, H Shepherd, C Guilleminault, T Sakai, WC Dement and E Mignot

Stanford Sleep Disorders Research Center, Palo Alto, California.

Recent experiments have demonstrated that pharmacological activation of central noradrenergic systems by monoaminergic stimulators or uptake blockers or through the stimulation of alpha-1 adrenergic receptors improved cataplexy, a major symptom of narcolepsy. In order to further the understanding of the control of cataplexy by noradrenergic mechanisms, the involvement of central alpha-2 adrenoceptors was examined in genetically narcoleptic Doberman pinschers using in vivo pharmacology. Yohimbine (1.5-96.0 micrograms/kg i.v.) and seven other selective and centrally acting alpha-2 adrenoceptor antagonists (rauwolscine: 1.5-96 micrograms/kg i.v.; atipemazole: 1.5-96 micrograms/kg i.v.; Wy-25309: 1.5-386 micrograms/kg i.v.; CGS-7525A: 1.5-386 micrograms/kg i.v.; idazoxan, 6-1536 micrograms/kg i.v.; piperoxan, 6-1536 micrograms/kg i.v.; and mianserin, 6-1536 micrograms/kg i.v.) significantly suppressed cataplexy. The alpha-2 mediation of this effect was demonstrated by a close correlation between drug affinities (Ki) toward the alpha-2 site (defined using [3H]yohimbine in canine cortex) and the ability of these drugs to reduce cataplexy [ED50 in nanomoles per kilogram i.v.) (r2 = 0.71, n = 8, P less than .01). The effects of six centrally acting alpha-2 agonists on canine cataplexy were also examined and two groups of compounds were distinguished on the basis of their pharmacological profile. Classical alpha-2 agonists such as clonidine (0.0625-4.0 micrograms/kg i.v.), p-aminoclonidine (0.0625-4.0 micrograms/kg i.v.) and guanfacine (0.0625-4.0 micrograms/kg i.v.) had no effect on cataplexy whereas BHT-920 (0.01875-3.0 micrograms/kg i.v.), BHT-933 (16.0-258 micrograms/kg i.v.) and xylazine (16.0-258 micrograms/kg i.v.) dramatically aggravated cataplexy.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 253, Issue 3, pp. 1145-1152, 06/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


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J Psychopharmacol, January 1, 1993; 7(3): 293 - 294.
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