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

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. We thank Haruki Kasahara, Shunsuke Nakajima, Shudo Yoshida, and Rei Takahashi for their assistance on animal care.

The authors used ChatGPT (OpenAI) to improve the clarity and readability of the manuscript. All authors reviewed and approved the final version of the manuscript and take full responsibility for its content. This research was supported by JSPS KAKENHI 23H02787 (KT), 23K27478 (KT), 23K22376 (KT), 24H00729 (KT), 26K00589 (KT), 26K22216 (KT), 24K16869 (KY), 24KJ0069 (KY), 24K06626 (KH), 25KJ0306 (KH), 25K21230 (YT), 24KK0210 (YT), and 24KJ1927 (YT); the Keio Academic Development Fund (KT); the Keio Gijuku Fukuzawa Memorial Fund (KT); the Smoking Research Foundation (KT); and the HOKUTO Foundation for the Promotion of Biological Science.

Department of Psychology, Keio University, Tokyo, Japan Hiroto Inoue, Mizuki Yamamoto, Yuta Tamai, Shuntaro Matsushima, Kazuko Hayashi & Koji Toda Department of Otolaryngology-Head and Neck Surgery, Hearing Research Centre, University of Tübingen, Tübingen, Germany Japan Society for the Promotion of Science, Tokyo, Japan Yuta Tamai, Kota Yamada & Kazuko Hayashi Institute for Quantitative Biosciences, University of Tokyo, Tokyo, Japan The authors declare no competing interests. The experimental and housing protocols adhered to the Japanese National Regulations for Animal Welfare and were approved by the Animal Care and Use Committee of Keio University. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.