Journal
BIOLOGICAL PSYCHIATRY
Volume 72, Issue 6, Pages 457-465Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2012.03.010
Keywords
Anxiety; depression; ghrelin; hypothalamic-pituitary-adrenal axis; knockout; stress
Categories
Funding
- Project Grant from the National Health and Medical Research Council of Australia [1011274]
- Discovery Project Grant from the Australian Research Council (ARC) [DP109339]
- Monash Fellowship, Monash University
- National Health and Medical Research Council Peter Doherty Research Fellowship [465167]
- Endocrine Society of Australia Postdoctoral Fellowship
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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-opiomelano-cortin 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.
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