Tuesday, March 12, 2024

PDE4B activity is necessary for the cross-sensitization between binge-eating and drinking

12:00 PM

4464 East Hall

Biopsychology Colloquium featuring Dr. Karen Szumlinski, Professor of Psychological and Brain Sciences, UC Santa Barbara.

A high rate of co-morbidity exists between binge-eating and binge-drinking disorders, suggesting a common neuropathology.

Karen Szumlinski, Ph.D.

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 GWAS study of humans, implicating PDE4B as a potential contributor to the shared genetic risk between these disorders.

To begin to address this possibility, we developed a mouse model of co-morbid binge-eating and -drinking, using C57BL/6NJ (B6NJ) mice in which mice undergo 10 days of binge-eating (5 days/week), followed by 10 days of binge-drinking. Relative to chow-fed controls, females exhibit a cross-sensitization between binge-eating and -drinking that is apparent on the first day of alcohol-access, while a cross-sensitization emerges in male subjects over the course of alcohol-drinking. Immunoblotting conducted on 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.

Two experiments were conducted to test the functional relevance of this protein increase for cross-sensitization. In the first, acute pretreatment with 1.0 mg/kg of the PDE4B inhibitor A33 reduced the cross-sensitization observed in binge-eating females on day 1 of binge-drinking, without impacting this initial alcohol intake in males. In the second, we replicated the female-selective block of initial cross-sensitization in females and this effect was maintained during daily A33 pretreatment for 5 days. The 5-day A33 pretreatment regimen also lowered the cross-sensitization that occurred in males during repeated bouts of binge-drinking. The A33 effect did not persist upon cessation of pretreatment, however chow-fed mice with a prior A33 history exhibited elevated alcohol intake during the week following A33 pretreatment. These data provide evidence that elevated PDE4B signaling is necessary for the manifestation of the cross-sensitization between binge-eating and -drinking in both males and females, posing selective PDE4B inhibitors as potential therapeutic interventions for treating comorbid AUD and binge-eating disorders.