The effects of the recently identified neuropeptides orexin-A and orexin-B on the hypothalamic-pituitary-adrenal (HPA) system were investigated. An in vivo system was used to assess the central effects of both orexin-A and orexin-B. Different doses of the orexins (2.8-560 pmol) were administered intracerebroventricularly (i.c.v.) to adult male rats, and plasma corticosterone was used as an index of the degree of the activation of the HPA system. Both peptides exhibited a clear dose-response action, although orexin-B proved to be less effective than orexin-A. Pretreatment with the corticotropin-releasing hormone (CRH) antagonist alpha-helical CRH9-41 completely prevented the action of the orexins. Orexin-A, orexin-B or adrenocorticotropic hormone (ACTH) was further administered intraperitoneally (i.p.). While ACTH evoked a significant adrenal response, the orexins did not influence the basal secretion. Adrenal slices, oxygenized and perifused with Krebs' solution, were also treated with orexin-A, orexin-B or ACTH. Both orexins failed to modify the release of corticosterone, but ACTH induced a marked adrenal response. This study suggests that these appetite-regulating peptides might activate the HPA system at a central level but neither orexin-A nor orexin-B appears to modulate directly the adrenal corticosterone release.

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The role of neuropeptide Y (NPY) in the mediation of orexin-induced hypothalamic-pituitary-adrenal (HPA) activation was investigated in the rat. The HPA system was stimulated by intracerebroventricular (i.c.v.) administration of orexin-A or orexin-B (140 or 280 pmol, respectively) and the plasma concentration of corticosterone was used as an index of the degree of activation. i.c.v. pretreatment with NPY antagonist or NPY antiserum (30 min or 24 h before orexin administration, respectively) inhibited the orexin-induced corticosterone release. The inhibitory actions of the antagonist and the antiserum were revealed by the dose-response curve; the highest concentrations practically abolished the HPA activation evoked by the orexins. These data suggest that the HPA system-stimulating effect of the orexins may be mediated by NPY.

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The effects of endomorphin-1 (EM1) on behavioral responses and on the hypothalamic-pituitary-adrenal system were investigated in mice. Locomotor activity was measured in an "open-field" apparatus, with parallel recording of the numbers of rearings and groomings. Different doses of the peptide (250 ng to 5 microg) were administered to the animals intracerebroventricularly 30 min before the tests. EM1 caused significant increases in the locomotor activity and the number of rearings. The effect of EM1 on the basal corticosterone secretion was also investigated. At a dose of 5 microg, the peptide significantly increased plasma corticosterone level. The corticotropin-releasing hormone (CRH) antagonist alpha-helical CRH9-41, applied 30 min prior to EM1 administration, completely abolished the increases in both locomotion and the number of rearings and attenuated the corticosterone release evoked by EM1. These results suggest that the EM1 -induced increases in locomotion and rearing activity as well as the pituitary-adrenal activation are mediated by CRH.

The members of the CRF peptide family, corticotropin-releasing factor (CRF), urocortin I (Ucn I), urocortin II (Ucn II) and urocortin III (Ucn III) coordinate endocrine and behavioral responses to stress. CRF has also been demonstrated to stimulate dopamine (DA) synthesis. In our study, a superfusion system was used to investigate the effects of this peptide family on striatal DA release following electrical stimulation. The involvement of the CRF receptors was studied by pretreatment of rat striatal slices with selective CRF antagonists. CRF and Ucn I increased the release of [(3)H]DA while Ucn II and Ucn III were ineffective. The CRFR1 antagonist antalarmin inhibited the [(3)H]DA release induced by electrical stimulation and enhanced by CRF and Ucn I. The CRFR2 antagonist astressin-2B was ineffective. These results suggest that CRF and Ucn I mediate DA release through the activation of CRFR1. Ucn II and Ucn III are not involved in this process.