Dinner for Two: Digging into how Ghrelin and Endocannabinoid Systems Interact in the Ventral Tegmental Area to Regulate Non-Homeostatic Feeding

Ghrelin, a hormone produced by the stomach during times of energy deficiency, potently enhances feeding by activating its receptor, the growth hormone secretagogue receptor (GHSR). In the brain, GHSRs are highly expressed within the hypothalamus (HYP) and ventral tegmental area (VTA), brain regions responsible for regulating hunger-driven and reward/motivated feeding, respectively. Interestingly, endogenous cannabinoids (i.e. endocannabinoids) induce similar feeding effects by stimulating cannabinoid receptors (CB-1Rs) in many of the same brain regions that highly express GHSRs, including the HYP and VTA. Recent evidence showed that ghrelin requires endocannabinoid signaling within the HYP to promote food intake. While independent GHSR or CB-1R activation within the VTA increases motivated feeding, it is not known whether the effects of ghrelin in the VTA are also dependent on the endocannabinoid system. This thesis aimed to determine if these systems interact within the VTA and to ascertain the extent and underlying mechanism by which CB-1R signaling may mediate the capacity of ghrelin to promote motivated feeding behaviours within this region. We determined that genetic disruption of GHSRs suppresses the gene expression of important endocannabinoid system proteins and lowers endocannabinoid levels within the VTA. Moreover, we demonstrated that pharmacological antagonism of VTA CB-1Rs attenuated the potent orexigenic and motivational capacity of intra-VTA ghrelin. Electrophysiological investigations indicated that CB-1R antagonism blocked the ability of ghrelin to promote excitatory drive to VTA dopamine neurons, but that ghrelin may independently and directly stimulate these neurons. Together, our data show that CB-1R signaling mediates ghrelin-induced motivated feeding behaviours in the VTA. Our findings suggest that, as in the HYP and VTA, ghrelin and endocannabinoid systems may interact in all brain regions where their receptors are jointly expressed.