Cross-Sensitization between Binge Eating and Binge Drinking in a Novel C57BL/6NJ Murine Model of Disease Comorbidity Requires PDE4B Activation

Abstract

There is a high rate of comorbidity between binge eating (BE) and binge drinking (BD) behaviors, suggesting a common neuropathology. Recently, phosphodiesterase 4B ( PDE4B ) was identified as a pleiotropic gene associated with comorbid alcohol use disorder (AUD) and anorexia nervosa with BE in a genome-wide association study, implicating PDE4B as a potential contributor to shared genetic risk between these disorders. Here, we developed a novel mouse model of comorbid BE and BD in C57BL/6NJ mice in which mice underwent 10 d of BE, followed by 10 d of BD. Females exhibited cross-sensitization from BE to BD, which was apparent on the first day of ethanol access, whereas cross-sensitization emerged in males over multiple trials of BD. Accordingly immunoblotting of the nucleus accumbens tissue indicated a female-selective increase in PDE4B protein expression that was apparent on both the first and last day of BD in mice with a prior BE history. Acute pretreatment with the selective PDE4B inhibitor A33 (1.0 mg/kg) reduced the expression of cross-sensitization to BD in females on Day 1, and this effect was maintained during a 5 d A33 treatment regimen. The 5 d A33 treatment regimen also reduced expression of cross-sensitization to BD that had emerged in males over repeated sessions. These results provide preclinical, functional validation of PDE4B as a driver of food–ethanol cross-sensitization in a novel model for BE and BD comorbidity and support PDE4B in the shared genetic risk for these behavioral pathologies and as a target for pharmacotherapeutic intervention in comorbid AUD and BE behaviors.