Endocannabinoids acting on the cannabinoid-1 receptor (CB_1R) or ghrelin acting on its receptor (GHS-R1A) both promote alcohol-seeking behavior, but an interaction between the two signaling systems has not been explored. Here, we report that the peripheral CB_1 R inverse agonist JD5037 reduces ethanol drinking in wild-type mice but not in mice lacking CB_1R, ghrelin peptide or GHS-R1A- JD5037 treatment of alcohol-drinking mice inhibits the formation of biologically active octanoyl-ghrelin without affecting its inactive precursor desacyl-ghrelin. In ghrelin-producing stomach cells, JD5037 reduced the level of the substrate octanoyl-carnitine generated from palmitoyl-camitine by increasing fatty acid (3-oxidation. Blocking gastric vagal afferents abrogated the ability of either CB_1R or GHS-R-ia blockade to reduce ethanol drinking. We conclude that blocking CB_1R in ghrelin-producing cells reduces alcohol drinking by inhibiting the formation of active ghrelin and its signaling via gastric vagal afferents. Thus, peripheral CB_1R blockade may have therapeutic potential in the treatment of alcoholism.
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