The novel AMPA glutamate receptor antagonist zampaxidol attenuates binge eating potentiated by foot-shock stress

Abstract

Introduction: Binge eating is linked to the brain reward system, modulated by glutamatergic projections affecting the mesolimbic dopamine pathway. This study explored AMPA receptor antagonists' effects on binge eating and stress-induced feeding behavior. The aim was to investigate the effects of the GluA1 AMPA receptor antagonist zampaxidol (IEM-2131) and the reference compound IEM-1460 in a binge eating model, and to demonstrate zampaxidol's antagonistic activity at AMPA receptors.

Materials and Methods:  vivo experiments were performed on 42 adult male Wistar rats (250–300 g) divided into three groups (n = 14): intact control, IEM-1460 (3 mg/kg, i.p.), and zampaxidol (1 mg/kg, i.p.). In vitro experiments were conducted on 16 isolated Danio rerio neurons. Foot shock was used as stress. Antagonists' effects on kainic acid-induced ionic currents were examined via patch clamp.

Results and Discussion: Zampaxidol and IEM-1460 reduced mean chocolate mixture consumption to 11.5 ± 1.6 g and 10.0 ± 0.9 g, respectively, significantly lower than in the no-intervention group (15.9 ± 0.5 g) and the foot-shock-only group (18.6 ± 0.9 g). Both compounds produced a pronounced blocking effect on AMPA receptors. Zampaxidol's IC50 was 0.65 ± 0.27 μM.

Conclusions: The findings highlight the essential role of GluA1 AMPA receptors in food addiction. IEM-1460 (3 mg/kg, i.p.) and zampaxidol (1 mg/kg, i.p.) demonstrated high efficacy in a rat binge eating model potentiated by foot-shock stress. AMPA receptor antagonists may be useful for treating psychogenic stress-induced binge eating.

Graphical Abstract