Orexin receptor subtype activation and locomotor behaviour in the rat

Abstract

Orexin-producing neurones, located primarily in the perifornical region of the lateral hypothalamus, project to a wide spectrum of brain sites where they influence numerous behaviours as well as modulating the neuroendocrine and autonomic responses to stress. While some of the actions of orexin appear to be mediated via the type 1 receptor, some are not, including its action on the release of one stress hormone, prolactin. We describe here the ability of orexin to increase locomotor behaviours and identify the importance of both receptor subtypes in these actions. Rats were tested for their behavioural responses to the central activation of both the type 1 (OX(1)R) and type 2 (OX(2)R) receptor (ICV orexin A), compared to OX(2)R activation using a relatively selective OX(2)R agonist in the absence or presence of an orexin receptor antagonist that possesses highest affinity for OX(1)R. Increases in locomotor activity were observed, effects which were expressed by not only orexin A, which binds to both the OX(1)R and the OX(2)R receptors, but also by the relatively selective OX(2)R agonist [(Ala(11), Leu(15))-orexin B]. Furthermore, the OX(1)R selective antagonist only partially blocked the action of orexin A on most locomotor behaviours and did not block the actions of [(Ala(11), Leu(15))-orexin B]. We conclude that orexin A exerts its effects on locomotor behaviour via both the OX(1)R and OX(2)R and that agonism or antagonism of only one of these receptors for therapeutic purposes (i.e. sleep disorders) would not provide selectivity in terms of associated behavioural side effects.