Orexin/Hypocretin Receptor Subtypes: Cardiovascular And Behavioral Effects

Cerebroventricular administration of orexin A (ORX-A, hypocretin-1) results in increased mean arterial pressure (MAP) and locomotor activity. We determined the contribution of both orexin receptor subtypes in these responses. A chronic indwelling lateral cerebroventricular cannula (7 days) and an aortic catheter (24 hr) were implanted in Sprague-Dawley rats (250-300 g, males). Testing was conducted under unanesthetized, unrestrained conditions in a quiet room. Neither the orexin type 1 (OX1R, SB-408124, Sigma, n=9) nor the orexin type 2 (OX2R, Ala11, D-Leu15-Orexin-B, Tocris, n=8) by themselves altered MAP when injected i.c.v. (3 nanomoles). Antagonism of either the OX1R or OX2R, however, significantly attenuated the rise in MAP observed following administration of ORX-A (3 nanomoles, n=17). In neither case (OX1R or OX2R antagonist pretreatment) did the response to ORX-A given 5 minutes after the antagonist attain significance (within group ANOVA) and values similarly did not differ from those present in the same animals when treated with the antagonists by themselves (between group ANOVA). Open field behavior was recorded for 1 hr prior to i.c.v. injection of ORX-A alone, the antagonists alone, of the antagonists prior to ORX-A. Behavior was then monitored for 2 hr. ORX-A dose dependently increased total locomotor activity in these animals, behavior that lasted for at least 2 hr. The antagonists by themselves did not significantly alter total locomotor activity when compared to vehicle injected controls; however, both OX1R and OX2R pretreatment significantly reduced the magnitude and shortened the duration of the locomotor effect of ORX-A. These data provide evidence for the involvement of both ORX receptor subtypes in the cardiovascular and behavioral actions of the orexins. Supported by NIH HL 068652.