The results of this study support the involvement of endogenous ghrelin in regulation of alcohol consumption and shed light on the neuroanatomical substrate of this effect. First, we confirmed previous findings showing that ghrelin receptor antagonists reduce alcohol consumption. D-Lys3-GHRP-6, the GHSR 1a antagonist that we used, acted similarly to the antagonists used by Jerlhag et al. (2009b) and reduced preference to alcohol and alcohol intake in C57BL/6J mice in two DID paradigms. Second, immunohistochemical studies for c-Fos showed that D-Lys3-GHRP-6 decreased the neuronal stimulation induced by ethanol in the pIIIu only, while having no similar effects in the VTA or the Arc. D-Lys3-GHRP-6 did not affect blood ethanol concentrations after a systemic ethanol injection, thereby eliminating effects on metabolism as a possible explanation for our c-Fos data. These results indicate that endogenous ghrelin may act via the pIIIu to regulate alcohol consumption.
