Effects of Orexins on the Hypothalamic‐Pituitary‐Adrenal System

Abstract

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.

Interaction between the Corticotropin-Releasing Factor System and Hypocretins (Orexins): A Novel Circuit Mediating Stress Response

“…Footshock-sensitive neurons in lateral hypothalamus have been described that project to the PVN (Li and Sawchenko, 1998). Furthermore, hypocretin-1 induces c-Fos expression in the PVN (Ida et al, 2000a) and dose dependently stimulates ACTH and corticosterone release (Hagan et al, 1999;Ida et al, 2000a;Jaszberenyi et al, 2000;Kuru et al, 2000;Samson et al, 2002). Pretreatment with ␣-helical CRF, a CRF antagonist, blocks the corticosterone elevation induced by hcrt (Ida et al, 2000b;Jaszberenyi et al, 2000;Samson et al, 2002).…”

Cardiovascular effects of hypocretin-1 in nucleus of the solitary tract

“…On the other hand, the Hcrt projections to the NTS may function to modulate the activity of visceral afferents and/or to provide a general activation of the parasympathetic system during the digestive and absorptive phases of ingestion. However, it is now clear that orexin systems are not only involved in ingestive behaviors, but also exert an effect on a variety of physiological mechanisms involved in homeostasis (3,13,19,21,23,25,42,44,45,48). Therefore, it is possible that orexigenic pathways may function to adjust cardiovascular responses to activation of these different homeostatic mechanisms (10,12,15,33,42).…”

“…Although both Hcrt-1 and -2 have been shown to have similar physiological effects when administered centrally, Hcrt-1 appears to exert a more potent effect on most of these physiological variables (10,12,33,42,47). Hcrt-1 injections into the brain have been shown to increase feeding and drinking behaviors; produce sleep, wakefulness, and arousal disturbances; produce analgesia; activate the hypothalamic-pituitary axis; elicit gastric acid secretion; and alter temperature regulating mechanisms (3,14,19,21,23,25,42,44,45,48). Hcrt-1 neurons have been shown to contribute to an extensive innervation of forebrain, brain stem, and spinal cord structures (10,33,42,46,47), and receptors to Hcrt-1 have been demonstrated throughout the neuraxis (28).…”

Hypocretin/Orexin Selectively Increases Dopamine Efflux within the Prefrontal Cortex: Involvement of the Ventral Tegmental Area

“…Moreover, dysregulated HCRT neurotransmission is associated with the sleep/ arousal disorder narcolepsy (for reviews, see Hungs and Mignot, 2001;Scammell, 2001). In addition, central HCRT administration increases indices of both stressful and appetitive states, suggesting that HCRT may also participate in physiological and behavioral processes associated with high-arousal environmental conditions (Sakurai et al, 1998;Ida et al, 2000;Jaszberenyi et al, 2000;Samson et al, 2002;España et al, 2003). Combined, these observations suggest a pivotal role for the HCRT system in the regulation of behavioral state and state-dependent processes associated with alert, active waking.…”

“…For example, the feedingpromoting actions of HCRT may reflect a potentially broader role of HCRT in appetitive processes (Willie et al, 2001). Additionally, ICV HCRT-1 elicits a variety of stresslike physiological and behavioral responses, including activation of the hypothalamo-pituitary-adrenal axis (Jaszberenyi et al, 2000;Kuru et al, 2000), increased c-fos expression (España et al, 2003), locomotor activation, grooming, and the chewing of inedible material (Nakamura et al, 2000;España et al, 2001). Intra-VTA infusions of HCRT-1 also provoked certain stress-like behaviors, including grooming.…”