Requirement of central ghrelin signaling for alcohol reward.

Abstract

Ghrelin, via ghrelin receptors (GHS-R1A) hypothalamus, has emerged as an important gut-brain signal for the control of energy balance. Recently we showed that ghrelin activates a key mesolimbic reward circuit involved in natural as well as drug-induced reinforcement, the cholinergic-dopaminergic reward link. By this route, ghrelin may increase the incentive value of signals associated with motivated behaviors of importance for survival such as food-seeking. Common mechanisms have been found to regulate food intake as well as alcohol consumption. We therefore hypothesize that ghrelin is required for alcohol reward. Here we found that central ghrelin administration (to brain ventricles or to specific tegmetal areas involved in reward) increased alcohol intake in a two bottle (alcohol/water) free choice limited access paradigm in mice.  By contrast, central or peripheral administration of ghrelin receptor (GHS-R1A) antagonists suppressed alcohol intake in this model. Alcohol-induced locomotor stimulation, accumbal dopamine release and conditioned place preference were consistently abolished in models of suppressed central ghrelin signaling: GHS-R1A knockout mice and mice treated with two different GHS-R1A antagonists. Moreover, a GHS-R1A antagonist reduces the intake of saccharin, a reward without calories, and does not induce a taste aversion in mice. Thus, central ghrelin signaling, via GHS-R1A, not only stimulates the reward system, but also is also required for stimulation of that system by rewards such as alcohol and saccharin. Our data suggest that the central ghrelin signaling system constitutes a novel potential therapeutic target for addictive behaviors, such as alcohol dependence.