Ghrelin Recruits the Endocannabinoid System to Modulate Food Reward.

Ghrelin enhances feeding by activating the growth hormone secretagogue receptor (GHSR). In the brain, GHSRs are expressed in regions responsible for regulating food motivation including the ventral tegmental area (VTA). Endogenous cannabinoids also promote food-seeking behaviors through the cannabinoid receptor-1 (CB-1Rs) in brain regions including the VTA. It is not known, however, if ghrelin and endocannabinoids interact in the VTA to produce these effects. We therefore examined if GHSR and CB-1R interact within the VTA to enhance food motivation. Results show that GHSR and CB-1R mRNA are expressed in the VTA cells in male and female rats and mice, with the GHSR being expressed in dopamine cells and the CB-1R being expressed primarily in nondopaminergic cells with no obvious sex differences. Ghrelin directly activated and increased excitatory tone onto dopamine cells of male and female mice. Male rats lacking fully functional GHSR signaling showed disrupted gene expression of transcripts important for regulating the synthesis, release, and degradation of endocannabinoids and lowered the levels of 2-arachidonoylglycerol (2-AG) within the VTA. Moreover, pharmacological antagonism of VTA CB-1Rs attenuates the orexigenic and appetitive effects of intra-VTA ghrelin in rats and blocks the ability of ghrelin to promote excitatory drive to VTA dopamine neurons. Finally, blocking the breakdown of cannabinoids in the VTA enhances the effects of ghrelin on food motivation. Together, our data show that ghrelin stimulates VTA dopamine cells and ultimately food motivation in part through a mechanism that involves endocannabinoid signaling at the CB-1R.