Differential effects of intra-ventral tegmental area ghrelin and glucagon-like peptide-1 on the stimulatory action of D-amphetamine and cocaine-induced ethanol intake in male Sprague Dawley rats.

In order to further elucidate the role of mesolimbic peptides in the expression of ethanol reward, the present study investigated the effects of ghrelin and glucagon-like peptide-1 (GLP-1) on ethanol intake, in addition to ethanol intake stimulated by systemic d-amphetamine or cocaine treatment. While a number of studies suggest that ghrelin plays an important role in mesolimbic reward, emerging data now indicate that GLP-1 receptor mechanisms inhibit reward signaling, possibly by directly or indirectly inhibiting ghrelinergic activity within the mesolimbic system. In the present study all rats were initially habituated to a 6% ethanol solution. We then demonstrated that intraperitoneal injections of d-amphetamine and cocaine increased ethanol intake compared to the vehicle condition. In subsequent testing we examined the effects of ventral tegmental area (VTA) ghrelin or vehicle paired with a fixed dose of d-amphetamine or vehicle. In separate rats we then investigated the impact of the GLP-1 agonist exendin-4 (Ex-4), injected into the VTA, on ethanol intake alone, or when Ex-4 was co-administered with d-amphetamine or cocaine. Our results indicated that VTA ghrelin significantly increased ethanol intake, and most importantly, potentiated the effect of d-amphetamine and cocaine on ethanol consumption. Conversely, VTA Ex-4 inhibited ethanol intake and antagonized the stimulatory effect of d-amphetamine and cocaine on ethanol consumption. In a final study we further demonstrated that VTA Ex-4 treatment significantly inhibited the combined stimulatory effects of ghrelin paired with d-amphetamine or ghrelin paired with cocaine. Overall our findings are consistent with a critical role for both ghrelin and GLP-1 receptor mechanisms in mesolimbic ethanol reward circuitry. Moreover, our results further suggest that ghrelin and GLP-1 modulate the stimulatory effect of psychostimulants on ethanol intake.

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

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.