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

Endocannabinoids acting on the cannabinoid-1 receptor (CB₁R) 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 CB₁R inverse agonist JD5037 reduces ethanol drinking in wild-type mice but not in mice lacking CB₁R, 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 CB₁R or GHS-R_1A blockade to reduce ethanol drinking. We conclude that blocking CB₁R in ghrelin-producing cells reduces alcohol drinking by inhibiting the formation of active ghrelin and its signaling via gastric vagal afferents. Thus, peripheral CB₁R blockade may have therapeutic potential in the treatment of alcoholism.