Ghrelin is a potent orexigenic
hormone that acts in the central nervous system to stimulate food intake via the
growth hormone secretagogue receptor (GHSR) that is abundantly expressed in the ventral tegmental area (VTA). Not only does
ghrelin modulate feeding behavior via a homeostatic mechanism, but numerous studies have identified
ghrelin as a key regulator of reward-based hedonic feeding behaviors. Nutritional states influence
ghrelin and GHSR expression as well as the behavioral sensitivity to reward-inducing stimuli. In the current study, we examined the role of
ghrelin at the VTA level in food intake in two different nutritional states, satiety and hunger, by using a restricted feeding model. In this model, rats were conditioned to a daily 3-h (h) feeding session on standard chow for 10days and a high-fat diet (HFD) was supplied either in the third hour after 2h of chow diet intake, or at the beginning of a daily meal on the test day. We found that intra-VTA microinjection of 1, 2, and 4μg of
ghrelin, induced a dose-related increase of 1h of reward-based feeding on HFD in sated rats, as well as a 24-h
body weight gain. The overconsumption stimulated by
ghrelin could be attenuated by 10μg of direct infusion of the
ghrelin receptor antagonist
D-Lys3-GHRP-6 into the VTA. Moreover, our data showed that the injection of 1, 2, and 4μg of
ghrelin in the VTA, enhanced fasting-induced
hyperphagia on HFD in a dose-related manner following a 21-h food restriction as well as a 24-h
body weight gain. Conversely,
hyperphagia on HFD that is potentiated by
ghrelin could be blocked by pretreatment with a 10-μg
D-Lys3-GHRP-6 intra-VTA microinjection. Collectively, these data demonstrate that
ghrelin signaling at the VTA level mediates both reward-based eating and fasting-induced
hyperphagia and provides a primary target for the control of the intake of rewarding food.