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Biol Psychiatry. 2012 Sep 15;72(6):457-65. doi: 10.1016/j.biopsych.2012.03.010. Epub 2012 Apr 21.

Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress.

Author information

1
Department of Physiology, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia.

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.

PMID:
22521145
DOI:
10.1016/j.biopsych.2012.03.010
[Indexed for MEDLINE]

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