CB1 receptors on a subset of vagal afferent neurons modulate voluntary ethanol intake in mice

Gut-brain signaling influences alcohol consumption and addiction behaviors. We found that selectively deleting cannabinoid receptor 1 (CB1R) from advillin+ peripheral sensory neurons eliminates the inhibitory effect of the peripheral CB1R antagonist JD5037 on voluntary ethanol intake (VEI). Similar results were seen in mice with CB1R deletion in Phox2b+ nodose ganglia (NGA), but not in Wnt+ dorsal root ganglia. These findings were corroborated with MRI-1891, another non-brain penetrant CB1R antagonist. The inhibition of VEI by JD5037 was lost in Gpr65Cre;Cnr1lox/lox mice but remained intact in Glp1rCre;Cnr1lox/lox mice. Additionally, deleting the ghrelin receptor (Ghsr) from Phox2b+ NGA neurons blocked the inhibition of alcohol intake either by a Ghsr or by CB1R antagonists. Thus, CB1R on Gpr65+ NGA projections to the mucosa of the gastrointestinal tract is essential for VEI. These findings also suggest a mutual interdependence of endocannabinoid and ghrelin signaling in controlling VEI via a gut-brain axis.