The selective OX1R antagonist 1-SORA-51 reduces binge-like feeding behavior in male and female mice without detectable changes in dopamine.

Binge eating disorder (BED) is characterized by episodic overconsumption of palatable food and involves dysregulated motivational and arousal processes. The orexin (hypocretin) system, through its widespread projections to mesolimbic circuits, has been implicated in cue-driven reward seeking and escalated intake, raising the possibility that orexin receptor antagonists may modulate binge-like behavior. Here we evaluated the effects of a dual orexin receptor antagonist (DORA-22) and an OX1R-selective antagonist (1-SORA-51) in a cyclic intermittent high-fat access model that generates robust and reproducible binge-like intake in male and female mice. DORA-22 produced no detectable effect on consumption at either early (2 h) or extended (24 h) binge timepoints. In contrast, 1-SORA-51 significantly reduced high-fat intake during the initial 2 hours of access in both sexes, with no effect on 24-hour consumption, indicating a selective attenuation of the early phase of binge intake. Fiber photometry recordings of GRABDA2m fluorescence in the nucleus accumbens revealed that 1-SORA-51 did not alter baseline dopamine signals or the dopamine increase triggered by high-fat pellet delivery, demonstrating that its behavioral effects occur without detectable modulation of mesolimbic dopamine dynamics. Together, these findings identify OX1R antagonism as a strategy for suppressing the initiation of binge-like feeding and highlight the receptor-level specificity of orexin contributions to maladaptive overconsumption.