Systemic administration of the mGluR2/3 antagonist LY341495 disrupts reward-related behaviors across ingestive and social domains in mice

Abstract Metabotropic glutamate 2/3 receptors (mGluR2/3) have been implicated in depression, anxiety, learning, and memory, yet their role in reward-related behavior remains poorly understood. Here, we examined the effects of the selective mGluR2/3 antagonist LY341495 on reward-related behaviors in mice using a combination of head-fixed and freely moving behavioral paradigms. In a head-fixed temporal conditioning task, mice developed anticipatory licking and pupil dilation preceding the delivery of a 10% sucrose solution, indicating successful temporal anticipation of reward. Systemic administration of LY341495 dose-dependently reduced both anticipatory and consummatory licking. Normalization analyses further suggested that LY341495 reduced the overall expression of licking behavior while largely preserving its temporal organization. LY341495 also induced pupil dilation and attenuated reward-proximity–related pupillary modulation. To determine whether these effects reflected non-specific motor impairments, we assessed locomotor activity in an open-field task and measured ultrasonic vocalizations (USVs) during courtship interaction. LY341495 did not significantly alter locomotion, excretion, or USV production, suggesting preserved general motor and orofacial motor function. In contrast, LY341495 dose-dependently reduced food intake and decreased social preference, indicating that the effects of mGluR2/3 antagonism extend beyond ingestive behavior to social reward-related processes. These findings demonstrate that mGluR2/3 signaling contributes to the regulation of reward-related behaviors across multiple reward domains independently of general motor dysfunction. These results provide new insight into glutamatergic mechanisms underlying motivation and reward processing and may have implications for neuropsychiatric disorders characterized by anhedonia and motivational deficits.