AbstractIntroductionIncreased glutamate levels and electrolytic fluctuations have been observed in acutely manic patients. Despite some efficacy of the non‐competitive NMDA receptor antagonist memantine (Mem), such as antidepressant‐like and mood‐stabilizer drugs in clinical studies, its specific mechanisms of action are still uncertain. The present study aims to better characterize theDrosophila melanogasterflyShakermutants (SH), as a translational model of manic episodes within bipolar disorder in humans, and to investigate the potential anti‐manic properties of Mem.Methods and ResultsOur findings showed typical behavioral abnormalities in SH, which mirrored with the overexpression of NMDAR‐NR1 protein subunit, matched well to glutamate up‐regulation. Such molecular features were associated to a significant reduction of SH brain volume in comparison to Wild Type strain flies (WT). Here we report on the ability of Mem treatment to ameliorate behavioral aberrations of SH (similar to that of Lithium), and its ability to reduce NMDAR‐NR1 over‐expression.ConclusionsOur results show the involvement of the glutamatergic system in the SH, given the interaction between theShakerchannel and the NMDA receptor, suggesting this model as a promising tool for studying the neurobiology of bipolar disorders. Moreover, our results show Mem as a potential disease‐modifying therapy, providing insight on new mechanisms of action.