Effects of centrally administered orexin-1 and orexinA: a role for orexin-1 receptors in orexin-B-induced hyperactivity

Rationale: Orexin-A and orexin-B are hypothalamic neuropeptides derived fro m a 130-amino acid precursor, prepro-orexin, and are potent agonists at bot h the orexin-1 (OX1) and orexin-2 (OX2) receptors. Orexin-A has been ascrib ed a number of in vivo functions in the rat after intracerebroventricular ( ICV) administration, including hyperphagia, neuroendocrine modulation and a role in the regulation of sleep-wake function. The in vivo role of orexin- B is not as clear. Objectives: To investigate the behavioural, endocrine an d neurochemical effects of orexin-B in in-vivo tests. In a number of experi ments, these effects were compared with those of orexin-A. Methods: Experim ents were carried out in male, Sprague-Dawley rats with a guide cannula dir ected towards the lateral ventricle. The effects of orexin-B (ICV) upon gro oming behaviour were compared with those of orexin-A. The effects of orexin -B upon the motor activity response to both novel and familiar environments were assessed in an automated activity monitor. Orexin-B was tested upon s tartle reactivity and body temperature. Further, plasma hormones and [DOPAC + HVA]/[DA] and [5-HIAA]/[5-HT] ratios in six brain areas were measured 40 min post-orexin-B or orexin-A. Results: The dearest behavioural response to orexin-B was increased motor activity in both novel and familiar environme nts. Orexin-B-induced hyperactivity was blocked by an OX1 receptor antagoni st, Sb-334867-A, implicating OX, receptors in this behavioural response. In common with orexin-A, orexin-B reduced plasma prolactin and failed to infl uence startle reactivity. However, in contrast with orexin-A, orexin-B incr eased head grooming but failed to cause a robust whole body grooming respon se or increase plasma corticosterone levels. Further, orexin-B, but not ore xin-A, increased plasma TSH and increased hypothalamic and striatal [5-HIAA ]/[5-HT] ratios. Conclusions: The present study has demonstrated a number o f behavioural, neuroendocrine and neurochemical effects of orexin-B that di stinguish it from orexin-A. Further, we have demonstrated a role for OX1 re ceptors in the actions of orexin-B upon motor activity.