Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite

TLDR

Ghrelin, through its receptor GHSR, acts on the ventral tegmental area to influence feeding and energy balance. In mice and rats, ghrelin binding to VTA neurons elevates dopamine activity, promotes synaptogenesis and dopamine turnover in the nucleus accumbens, and drives feeding, effects that are blocked by a GHSR antagonist and diminished in GHSR‑deficient animals.

Abstract

The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling energy metabolism as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding. Here we show that in mice and rats, ghrelin bound to neurons of the VTA, where it triggered increased dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens in a GHSR-dependent manner. Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting. In addition, ghrelin- and GHSR-deficient mice showed attenuated feeding responses to restricted feeding schedules. Taken together, these data suggest that the mesolimbic reward circuitry is targeted by peripheral ghrelin to influence physiological mechanisms related to feeding.