Ghrelin alters the stimulatory effect of cocaine on ethanol intake following mesolimbic or systemic administration

•Systemic administration of cocaine increases ethanol intake.•Ghrelin stimulates ethanol intake.•Systemic and direct VTA injections of ghrelin potentiate cocaine's effects.

Emerging evidence suggests that ghrelinergic and dopaminergic signaling interact in the neural control of motivation and ethanol reward. To further investigate a possible interaction between these two neurochemical systems, we examined the impact of ghrelin, cocaine and combined injections of ghrelin with cocaine, on voluntary ethanol intake. Male Sprague-Dawley rats were habituated to an 8% ethanol solution until intakes stabilized. Rats were then injected with ghrelin (2.5-10 nmol IP), cocaine (0.625-10 mg/kg IP) or ghrelin paired with cocaine. We also examined the impact of direct ghrelin (30-300 pmol) injections into the ventral tegmental area (VTA) co-administered with systemic cocaine. Ethanol consumption was measured at 2 and 6 h postinjection. While ghrelin and cocaine reliably increased ethanol intake, peripheral administration of the peptide elicited a dose-dependent differential effect on cocaine-induced intake. Pretreatment with ghrelin potentiated the effect of cocaine on ethanol intake at a low dose of 2.5 nmol, whereas 10 nmol suppressed cocaine-induced ethanol intake. This same 10 nmol dose was found to induce anxiogenic behavior as measured using an elevated plus maze paradigm. Finally, when injected directly into the VTA, ghrelin (300 pmol) potentiated the effect of systemic cocaine on ethanol intake. Combined subthreshold dosing of VTA ghrelin with a subthreshold dose of cocaine also evoked reliable increases in intake compared to vehicle. Overall, our data suggest that low doses of ghrelin elicit a stimulatory effect on cocaine-induced ethanol consummatory behavior and provide further support for an interactive role of dopaminergic and ghrelinergic transmission in ethanol reward.