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

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Abstract Gut-brain signaling influences alcohol consumption and addiction behaviors. We found that selectively deleting cannabinoid receptor 1 (CB 1 R) from advillin + peripheral sensory neurons eliminates the inhibitory effect of the peripheral CB 1 R antagonist JD5037 on voluntary ethanol intake (VEI). Similar results were seen in mice with CB 1 R deletion in Phox2b + nodose ganglia (NGA), but not in Wnt + dorsal root ganglia. These findings were corroborated with MRI-1891, another non-brain penetrant CB 1 R 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 CB 1 R antagonists. Thus, CB 1 R 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.

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