Author: Spencer, S.J.; Xu, L.; Clarke, M.A.; Lemus, M.; Reichenbach, A.; Geenen, B.; Kozicz, T.; Andrews, Z.B.
Description: 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.
Subject Headings: Adrenocorticotropic Hormone/blood/metabolism; Analysis of Variance; Animals; Anxiety/metabolism; Corticosterone/blood/metabolism; Corticotropin-Releasing Hormone/metabolism; Dexamethasone/pharmacology; Ghrelin/genetics/physiology; Hypothalamo-Hypophyseal System/drug effects/physiology; Mice; Mice, Knockout; Pituitary-Adrenal System/drug effects/physiology; Receptors, Ghrelin; Restraint, Physical; Stress, Psychological/physiopathology
Publication year: 2012
Journal or book title: Biological Psychiatry
Volume: 72
Issue: 6
Pages: 457-465
Find the full text : http://pages.ucsd.edu/~mboyle/COGS163/pdf-files/Ghrelin%20Regulates%20the%20Hypothalamic-Pituitary-Adrenal%20Axis%20and%20Restricts%20Anxiety%20After%20Acute%20Stress.pdf
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Type: Journal Article
Serial number: 2749