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 Gpr65^Cre;Cnr1^lox/lox mice but remained intact in Glp1r^Cre;Cnr1^lox/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.