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Despite some efficacy of the non\u2010competitive NMDA receptor antagonist memantine (Mem), such as antidepressant\u2010like and mood\u2010stabilizer drugs in clinical studies, its specific mechanisms of action are still uncertain. The present study aims to better characterize the <jats:italic>Drosophila melanogaster<\/jats:italic> fly <jats:italic>Shaker<\/jats:italic> mutants (SH), as a translational model of manic episodes within bipolar disorder in humans, and to investigate the potential anti\u2010manic properties of Mem.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>Our findings showed typical behavioral abnormalities in SH, which mirrored with the overexpression of NMDAR\u2010NR1 protein subunit, matched well to glutamate up\u2010regulation. 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\u2010NR1 over\u2010expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results show the involvement of the glutamatergic system in the SH, given the interaction between the <jats:italic>Shaker<\/jats:italic> channel 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\u2010modifying therapy, providing insight on new mechanisms of action.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.14145","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T08:06:23Z","timestamp":1679385983000},"page":"1750-1761","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Effects of memantine on mania\u2010like phenotypes exhibited by <i>Drosophila Shaker<\/i> mutants"],"prefix":"10.1111","volume":"29","author":[{"given":"Ignazia","family":"Mocci","sequence":"first","affiliation":[{"name":"Institute of Translational Pharmacology National Research Council, Science and Technology Park of Sardinia  Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Antonietta","family":"Casu","sequence":"additional","affiliation":[{"name":"Institute of Translational Pharmacology National Research Council, 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