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

Abstract

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)

• Authors: S Nishino, L Haak, H Shepherd, C Guilleminault, T Sakai, W C Dement, E Mignot
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 253 Issue 3 Pg. 1145-52 (Jun 1990) ISSN: 0022-3565 [Print] United States
• PMID: 1972749 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adrenergic alpha-Agonists
• Adrenergic alpha-Antagonists
• Receptors, Adrenergic, alpha
• Yohimbine

Topics

• Adrenergic alpha-Agonists (metabolism, pharmacology)
• Adrenergic alpha-Antagonists (metabolism, pharmacology)
• Animals
• Binding, Competitive
• Cataplexy (drug therapy)
• Cerebral Cortex (drug effects, metabolism)
• Dogs
• Hemodynamics (drug effects)
• Injections, Intravenous
• Receptors, Adrenergic, alpha (drug effects, metabolism)
• Sleep, REM (drug effects)
• Yohimbine (metabolism, therapeutic use)