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 type (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 non-dopaminergic 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 signalling 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 signalling at the CB-1R. Significance Statement The current paper utilized a molecular, cellular and behavioral set of approaches to explore the interaction between the ghrelin and endocannabinoid systems in dopamine cells in the VTA. Our results not only confirm that ghrelin activates VTA dopamine neurons, and increases food motivation in rodents, but also that this interaction is in part mediated by the activation of the endocannabinoid system. We demonstrate that blocking the CB-1R in the VTA attenuates the effects of ghrelin on reward seeking behaviors and excitatory tone onto VTA dopamine neurons. Importantly, reducing enzymatic degradation of endocannabinoids enhances the effects of a sub-threshold dose of ghrelin. Overall, these data support the hypothesis that ghrelin interacts with endogenous cannabinoids to stimulate dopamine cells in the VTA.