The interaction of ghrelin and endocannabinoid systems within the VTA is necessary and important for the modulation of food intake

A. W. Edwards, S. Rosenbaum, A. Abizaid

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Ghrelin is a hormone that targets growth hormone secretagogue receptors (GHSR) in the brain to increase food intake and energy balance. Its ability to stimulate food intake is well known in the hypothalamus (HYP), a brain region integral to the modulation of feeding; however, evidence suggests that ghrelin also increases appetite by acting on GHSRs in the ventral tegmental area (VTA), a brain region associated with reward seeking behaviors. Interestingly, it has been shown that endogenous cannabinoids (i.e. endocannabinoids), like ghrelin, stimulate appetite within the HYP and that a functional endocannabinoid system (ECS) is required for ghrelin’s appetitive effects within this region. We hypothesize that a similar interaction between ghrelin and endocannabinoid systems exists in the VTA to modulate feeding. We predicted that if this interaction exists and is important in modulating feeding then there should be differences in cannabinoid receptor (i.e. CB-1R) expression between WT and rats which lack functional GHSR (i.e. GHSR KO), especially within important feeding nuclei (e.g. prefrontal cortex (PFC), hippocampus (HIP), nucleus accumbens (NA), HYP and VTA). To investigate this, these brain regions from Fawn hooded GHSR KO and WT rats were punched, processed, and analyzed via Real Time qPCR using the 2-[[unable to display character: &#8710;]][[unable to display character: &#8710;]]Ct method, to compare the relative expression of CB-1R mRNA. Although no significant differences in CB-1R expression were found within HYP, HIP, and NA regions (p > .05), GHSR KO rats had significantly lower VTA CB-1R mRNA expression but higher PFC CB-1R mRNA expression than WT rats (p < .05). Given that disrupting ghrelin signalling induced changes in CB-1R expression within the VTA we wanted to test whether a functional ECS was important for modulating ghrelin’s orexigenic effects within the VTA. To test this hypothesis, Long-Evans rats were cannulated and placed in one of the following 4 treatment groups (intraperitoneal/intra-VTA): vehicle/saline, rimonabant (1.5 mg/kg)/saline, vehicle/ghrelin (1 µg /0.5 µl), rimonabant (1.5 mg/kg)/ghrelin (1 µg /0.5 µl) to determine if global pharmacological inhibition of the cannabinoid system would attenuate the ability of ghrelin within the VTA to acutely increase food intake (measured 1, 2, 4, & 6 hours post-microinjection). Results demonstrated that ghrelin administered into the VTA significantly increased food intake (p < .05) and that this effect was attenuated to control levels when animals were pre-treated with rimonabant 30 minutes prior to ghrelin microinjections. This data ultimately suggests that ghrelin targets the VTA to increase food intake through an interaction with the CB system.