Ghrelin is an orexigenic peptide and elicits anxiety-like behaviors following administration into discrete regions of the hypothalamus

Previous evidence indicates that peripherally administered ghrelin significantly increases corticotropin releasing hormone (CRH) mRNA and serum corticosterone. In addition, intraventricular administration of ghrelin has been reported to elicit anxiety-like behaviors suggesting that the peptide plays a role in mediating neuroendocrine and behavioral responses to stress. In the present study, we characterized the orexigenic, metabolic, and anxiogenic actions of ghrelin following microinjection into the arcuate nucleus (ARN), paraventricular nucleus (PVN), perifornical hypothalamus (PFH), and ventromedial nucleus (VMN). To assess ghrelin's role in anxiogenic behavior, rats were injected with vehicle or 50–800 pmol of ghrelin and then placed in an elevated plus maze (EPM) for 10 min. Each test was performed as a single trial per animal. In separate behavioral testing we measured the induction of stereotypic behaviors. Doses of 200 pmol or higher administered into the ARN and PVN elicited anxiety-like behaviors, including an increased avoidance of the open arms of the EPM. However, in the PFH and VMN, higher doses of ghrelin (400–800 pmol) were required to induce anxiety. Ghrelin doses as low as 50 pmol stimulated eating and altered energy substrate oxidation (respiratory quotient; RQ) when injected into the ARN and PVN. Injections into the PFH and VMN elicited more modest effects on eating and RQ at doses of 400 pmol or greater. Our findings indicate that regions of the hypothalamus appear to be differentially sensitive and responsive to the feeding-stimulant, metabolic, and anxiogenic actions of ghrelin and that the ARN and PVN, in particular, exert a primary role in mediating these effects.

► Hypothalamic ghrelin elicits anxiety-like behaviors.
► Ghrelin is orexigenic in discrete hypothalamic nuclei.
► Hypothalamic ghrelin alters energy substrate oxidation.