Abstract
Ghrelin receptor (Ghr-R) signaling in neurons of the ventral tegmental area (VTA) can modulate dopaminergic function and the reward-related effects of both palatable foods and drugs of abuse. In this study, we re-introduced the Ghr-R in VTA neurons in Ghr-R knockout mice (Ghr-RVTA mice) to specifically study the importance of the constitutively active Ghr-R for VTA neuronal signaling. Our results showed that re-introduction of the Ghr-R in the VTA had no impact on body weight or food intake under basal conditions. However, during novel environment stress Ghr-RVTA mice showed increased food intake and energy expenditure compared to Ghr-R knockout mice, demonstrating the significance of Ghr-R signaling in the response to stress. Ghr-RVTA mice also showed increased cocaine-induced locomotor activity compared to Ghr-R knockout mice, highlighting the importance of ghrelin signaling for the reward-related effects of activation of VTA neurons. Overall, our data suggest that re-introduction of the Ghr-R in the mesolimbic reward system of Ghr-R knockout mice increases the level of activation induced by both cocaine and novelty stress.
Highlights
The gut hormone ghrelin exerts many different functions, but one of its most well-described roles is the regulation of metabolism and food intake, largely mediated by the arcuate nucleus of the hypothalamus [1]
We have previously demonstrated this effect, using a mouse model of virus-induced ghrelin receptor (Ghr-R) overexpression in the amygdala to evaluate the anxiolytic effect of Ghr-R signaling [22]
Ghrelin KO mice are hypo-responsive to the effects of cocaine, reflected in attenuated locomotor activity following both acute and chronic cocaine injections, compared to wild-type mice [33]. These behavioral effects correlate with cocaine-induced changes in dopamine turnover in the striatum of wild-type mice that are not seen in ghrelin KO mice unless pre-treated with ghrelin [33]
Summary
The gut hormone ghrelin exerts many different functions, but one of its most well-described roles is the regulation of metabolism and food intake, largely mediated by the arcuate nucleus of the hypothalamus [1]. Intra-VTA administration of a Ghr-R antagonist attenuates the ability of peripheral ghrelin to increase food intake, highlighting the importance of the mesolimbic system for the orexigenic effects of ghrelin [2]. Re-expression of the Ghr-R in dopaminergic neurons of Ghr-R KO mice partly restores ghrelin-induced food intake [30], underlining the significance of dopaminergic signaling for the orexigenic effect of ghrelin. Ghrelin KO mice are hypo-responsive to the effects of cocaine, reflected in attenuated locomotor activity following both acute and chronic cocaine injections, compared to wild-type mice [33] These behavioral effects correlate with cocaine-induced changes in dopamine turnover in the striatum of wild-type mice that are not seen in ghrelin KO mice unless pre-treated with ghrelin [33]. The Ghr-R has a high constitutive activity and the receptor re-introduction on its own may be sufficient to exert an effect independent of ghrelin availability [19]
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