Orexin 2 receptor regulation of the hypothalamic–pituitary–adrenal (HPA) response to acute and repeated stress

Abstract

Orexins are hypothalamic neuropeptides that have a documented role in mediating the acute stress response. However, their role in habituation to repeated stress, and the role of orexin receptors (OXR and OXR) in the stress response, has yet to be defined. Orexin neuronal activation and levels in the cerebrospinal fluid (CSF) were found to be stimulated with acute restraint, but were significantly reduced by day five of repeated restraint. As certain disease states such as panic disorder are associated with increased central orexin levels and failure to habituate to repeated stress, the effect of activating orexin signaling via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on the hypothalamic-pituitary-adrenal (HPA) response was evaluated after repeated restraint. While vehicle-treated rats displayed habituation of Adrenocorticotropic Hormone (ACTH) from day 1 to day 5 of restraint, stimulating orexins did not further increase ACTH beyond vehicle levels for either acute or repeated restraint. We delineated the roles of orexin receptors in acute and repeated stress using a selective OXR antagonist (MK-1064). Pretreatment with MK-1064 reduced day 1 ACTH levels, but did not allow further habituation on day 5 compared with vehicle-treated rats, indicating that endogenous OXR activity plays a role in acute stress, but not in habituation to repeated stress. However, in restrained rats with further stimulated orexins by DREADDs, MK-1064 decreased ACTH levels on day 5. Collectively, these results indicate that the OXR plays a role in acute stress, and can prevent habituation to repeated stress under conditions of high orexin release.

Orexin Depolarizes Central Amygdala Neurons via Orexin Receptor 1, Phospholipase C and Sodium-Calcium Exchanger and Modulates Conditioned Fear

“…To specifically activate this subgroup of CeA projecting fibers, we utilized a chemogenetic DREADD (Armbruster et al, 2007) under control of the prepro-OX gene promoter (Moriguchi et al, 2002). This virus has been previously validated to express DREADD-coupled G αq in OX neurons and stimulate release of OX in response to DREADD agonist clozapine-N-oxide (CNO) (Grafe et al, 2017).…”

“…Here, using OX receptor subtype-specific antagonists, C 56, a selective OXR1 antagonist (Bonaventure et al, 2015) and JNJ10397049, a selective OXR2 antagonist (Dugovic et al, 2009), and prepro-OX-DREADD (Grafe et al, 2017), we aimed to characterize the cellular, molecular, and behavioral consequences of OX signaling in the CeA.…”

Immune imbalance of global gene expression, and cytokine, chemokine and selectin levels in the brains of offspring with social deficits via maternal immune activation

“…POMC is a precursor neuropeptide that is cleaved to form adrenocorticotropic hormone. HCRT increases adrenocorticotropin‐releasing hormone levels and arginine‐vasopressin mRNA levels in the paraventricular nucleus of the hypothalamus . Up‐ or downregulation of the HPA activity affects growth, development and metabolism and ultimately leads to behavioral changes.…”

Reduced Orexin System Function Contributes to Resilience to Repeated Social Stress

“…In this respect, pre-existing differences in orexin expression impact future responses to stress. On the other hand, perhaps orexin function is also decreased with repeated exposure to social defeat in rats that become resilient to defeat; this is known to occur after repeated restraint stress ( Grafe et al, 2017b ). Currently, we are only able to measure cerebrospinal fluid levels of orexins terminally, and plasma levels of orexins are not a reliable indication of central orexin activity; thus, we cannot directly determine whether this difference in orexin expression predates exposure to stress.…”