Cross-sensitization between binge-eating and -drinking in a novel C57BL/6NJ murine model of disease co-morbidity requires PDE4B activation.

Abstract

There is a high rate of co-morbidity between binge-eating and binge-drinking 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 binge-eating in a genome-wide association study, implicating PDE4B as a potential contributor to shared genetic risk between these disorders. To address this possibility, we developed a novel mouse model of co-morbid binge-eating and -drinking in C57BL/6NJ mice in which mice underwent 10 days of binge-eating, followed by 10 days of binge-drinking. Females exhibited cross-sensitization from binge-eating to -drinking, that was apparent on the first day of ethanol access, whereas cross-sensitization emerged in males over multiple trials of binge-drinking. Accordingly immunoblotting of nucleus accumbens tissue indicated a female-selective increase in PDE4B protein expression that was apparent on both the first and last day of binge-drinking in mice with a prior binge-eating history. Acute pretreatment with the selective PDE4B inhibitor A33 (1.0 mg/kg) reduced the expression of cross-sensitization to binge-drinking in females on Day 1 and this effect was maintained during a 5-day A33 treatment regimen. The 5-day A33 treatment regimen also reduced expression of cross-sensitization to binge drinking 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 binge-eating and -drinking comorbidity and support PDE4B in the shared genetic risk for these behavioral pathologies and as a target for pharmacotherapeutic intervention in comorbid AUD and binge-eating behaviors.Significance statement Binge-eating and -drinking are highly comorbid pathological behaviors that complicate treatment and increase risk of other psychiatric/somatic conditions and mortality. We face a knowledge gap regarding the biological bases of this comorbidity to inform prognosis and treatment-based recovery. Herein, we developed a mouse model of binge-eating/drinking cross-sensitization and showed that 1) prior binge-eating history potentiated subsequent binge ethanol-drinking in both female and male C57BL/6NJ mice, 2) this behavioral cross-sensitization was associated with elevated expression of phosphodiesterase 4B (PDE4B) expression in the nucleus accumbens, and 3) reducing PDE4B activation via systemic pretreatment with a selective inhibitor prevented binge-eating/drinking cross-sensitization in mice of both sexes. Findings implicate enhanced PDE4B signaling in the etiology and treatment of co-morbid binge-eating and -drinking behaviors.