Effects of central alpha-2 adrenergic compounds on canine narcolepsy, a disorder of rapid eye movement sleep.
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)
Nishino
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S
Stanford Sleep Disorders Research Center, Palo Alto, California.
Haak
L
L
Shepherd
H
H
Guilleminault
C
C
Sakai
T
T
Dement
W C
WC
Mignot
E
E
D000316:Adrenergic alpha-Agonists / Q000378:metabolism / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D002385:Cataplexy / Q000188:drug therapy*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D007275:Injections, Intravenous; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism; D012895:Sleep, REM / Q000187:drug effects*; D015016:Yohimbine / Q000378:metabolism / Q000627:therapeutic use*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine