Glutamatergic regulation of ghrelin-induced activation of the mesolimbic dopamine system

Recently, we demonstrated that the central ghrelin signalling system, involving the ghrelin receptor (GHS-R1A), is important for alcohol reinforcement. Ghrelin targets a key mesolimbic circuit involved in natural as well as drug-induced reinforcement, that includes a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens. The aim of the present study was to determine whether it is possible to suppress ghrelin's effects on this mesolimbic dopaminergic pathway can be suppressed, by interrupting afferent inputs to the VTA dopaminergic cells, as shown previously for cholinergic afferents. Thus, the effects of pharmacological suppression of glutamatergic, orexin A and opioid neurotransmitter systems on ghrelin-induced activation of the mesolimbic dopamine system were investigated. We found in the present study that ghrelin-induced locomotor stimulation was attenuated by VTA administration of the N-methyl-D-aspartic acid receptor antagonist (AP5) but not by VTA administration of an orexin A receptor antagonist (SB334867) or by peripheral administration of an opioid receptor antagonist (naltrexone). Intra-VTA administration of AP5 also suppressed the ghrelin-induced dopamine release in the nucleus accumbens. Finally the effects of peripheral ghrelin on locomotor stimulation and accumbal dopamine release were blocked by intra-VTA administration of a GHS-R1A antagonist (BIM28163), indicating that GHS-R1A signalling within the VTA is required for the ghrelin-induced activation of the mesolimbic dopamine system. Given the clinical knowledge that hyperghrelinemia is associated with addictive behaviours (such as compulsive overeating and alcohol use disorder) our finding highlights a potential therapeutic strategy involving glutamatergic control of ghrelin action at the level of the mesolimbic dopamine system.