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

Endocannabinoids acting on the cannabinoid-1 receptor (CBR) or ghrelin acting on its receptor (GHS-R) both promote alcohol-seeking behavior, but an interaction between the two signaling systems has not been explored. Here, we report that the peripheral CBR inverse agonist JD5037 reduces ethanol drinking in wild-type mice but not in mice lacking CBR, ghrelin peptide or GHS-R. 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 CBR or GHS-R blockade to reduce ethanol drinking. We conclude that blocking CBR in ghrelin-producing cells reduces alcohol drinking by inhibiting the formation of active ghrelin and its signaling via gastric vagal afferents. Thus, peripheral CBR blockade may have therapeutic potential in the treatment of alcoholism.