title: 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 (OX1R and OX2R) 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 OX2R 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 OX2R 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 OX2R plays a role in acute stress, and can prevent habituation to repeated stress under conditions of high orexin release.
authors.affiliation: Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Grafe
authors.affiliation: Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Darrell
authors.initials: D
authors.lastname: Eacret
authors.affiliation: Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Luz
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Gotter
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.affiliation: Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Winrow
authors.affiliation: Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: bhatnagars@email.chop.edu.
authors.forename: Seema
authors.initials: S
authors.lastname: Bhatnagar
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D006185:Habituation, Psychophysiologic / Q000187:drug effects / Q000502:physiology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology*; D064446:Orexin Receptors / Q000378:metabolism*; D000068797:Orexins / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D000068797:Orexins; D000324:Adrenocorticotropic Hormone
keywords: DREADDs; MK-1064; habituation; hypocretin; orexin receptor; stress