Targeting Peripheral CB1 Receptors Reduces Ethanol Intake via a Gut-Brain Axis

Summary Endocannabinoids acting on the cannabinoid-1 receptor (CB 1 R) or ghrelin acting on its receptor (GHS-R 1A ) 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 1 R, ghrelin peptide or GHS-R 1A . 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-carnitine by increasing fatty acid β-oxidation. Blocking gastric vagal afferents abrogated the ability of either CB 1 R or GHS-R 1A blockade to reduce ethanol drinking. We conclude that blocking CB 1 R in ghrelin-producing cells reduces alcohol drinking by inhibiting the formation of active ghrelin and its signaling via gastric vagal afferents. Thus, peripheral CB 1 R blockade may have therapeutic potential in the treatment of alcoholism.