title: Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress.
abstract: BACKGROUND
  Ghrelin plays important roles in glucose metabolism, appetite, and body weight regulation, and recent evidence suggests ghrelin prevents excessive anxiety under conditions of chronic stress.
  
  
  METHODS
  We used ghrelin knockout (ghr-/-) mice to examine the role of endogenous ghrelin in anxious behavior and hypothalamic-pituitary-adrenal axis (HPA) responses to acute stress.
  
  
  RESULTS
  Ghr-/- mice are more anxious after acute restraint stress, compared with wild-type (WT) mice, with three independent behavioral tests. Acute restraint stress exacerbated neuronal activation in the hypothalamic paraventricular nucleus and medial nucleus of the amygdala in ghr-/- mice compared with WT, and exogenous ghrelin reversed this effect. Acute stress increased neuronal activation in the centrally projecting Edinger-Westphal nucleus in WT but not ghr-/- mice. Ghr-/- mice exhibited a lower corticosterone response after stress, suggesting dysfunctional glucocorticoid negative feedback in the absence of ghrelin. We found no differences in dexamethasone-induced Fos expression between ghr-/- and WT mice, suggesting central feedback was not impaired. Adrenocorticotropic hormone replacement elevated plasma corticosterone in ghr-/-, compared with WT mice, indicating increased adrenal sensitivity. The adrenocorticotropic hormone response to acute stress was significantly reduced in ghr-/- mice, compared with control subjects. Pro-opiomelanocortin anterior pituitary cells express significant growth hormone secretagogue receptor.
  
  
  CONCLUSIONS
  Ghrelin reduces anxiety after acute stress by stimulating the HPA axis at the level of the anterior pituitary. A novel neuronal growth hormone secretagogue receptor circuit involving urocortin 1 neurons in the centrally projecting Edinger-Westphal nucleus promotes an appropriate stress response. Thus, ghrelin regulates acute stress and offers potential therapeutic efficacy in human mood and stress disorders.
authors.affiliation: Department of Physiology, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Spencer
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Clarke
authors.forename: Moyra
authors.initials: M
authors.lastname: Lemus
authors.forename: Alex
authors.initials: A
authors.lastname: Reichenbach
authors.forename: Bram
authors.initials: B
authors.lastname: Geenen
authors.forename: Tamás
authors.initials: T
authors.lastname: Kozicz
authors.forename: Zane B
authors.initials: ZB
authors.lastname: Andrews
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D054439:Ghrelin / Q000235:genetics / Q000502:physiology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology*; D054440:Receptors, Ghrelin; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: D054439:Ghrelin; D054440:Receptors, Ghrelin; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone