Further characterization of the alpha-1 receptor subtype involved in the control of cataplexy in canine narcolepsy.
We have demonstrated previously that central noradrenergic mechanisms, especially postsynaptic alpha-1 receptors, are critically involved in the regulation of cataplexy, a pathological manifestation of rapid eye movement sleep atonia in narcolepsy. However, it has been shown recently that alpha-1 receptors constitute a heterogeneous population of binding sites, which is encoded by several distinct genes. In light of these findings, we investigated the possibility that the effect of alpha-1 compounds on cataplexy found in our previous study is mediated more specifically by certain alpha-1 receptor subtypes than by other subtypes. We therefore examined the effects of eight selective alpha-1 antagonists and five agonists on canine cataplexy and compared these with the affinities of the same compounds for the canine central alpha-1a and alpha-1b subtypes. The affinities of the compounds for the alpha-1 receptor subtypes were assessed by using [3H]prazosin receptor binding in combination with a 5-methylurapidil (an alpha-1a selective ligand) mask. Six of the eight alpha-1 antagonists tested exacerbated canine cataplexy, whereas all five agonists tested suppressed cataplexy. Furthermore, the potency (ED50 values) of the compounds on cataplexy significantly correlated with the affinity of the compounds for the alpha-1b binding site. These results are consistent with our earlier implication of the alpha-1 receptor mechanisms in the control of cataplexy and further suggest a specific involvement of the alpha-1b receptor subtype in these mechanisms.
Nishino
S
S
Sleep Research Center, Stanford University School of Medicine, Palo Alto, California.
Fruhstorfer
B
B
Arrigoni
J
J
Guilleminault
C
C
Dement
W C
WC
Mignot
E
E
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002385:Cataplexy / Q000209:etiology* / Q000517:prevention & control; D004285:Dogs; D066298:In Vitro Techniques; D009290:Narcolepsy / Q000188:drug therapy; D011224:Prazosin / Q000378:metabolism; D011942:Receptors, Adrenergic, alpha / Q000032:analysis / Q000502:physiology*; D011985:Receptors, Serotonin / Q000502:physiology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D011224:Prazosin