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Few studies suggest that antidepressants exert their effects by activating some signaling pathways, including the phosphatidylinositol 3-kinase (PI3K). Moreover, valproic acid (VPA) activates the PI3K pathway. Thus, here we investigated the antidepressant-like effect of VPA and if its effect is related to PI3K/Akt/mTOR activation.C57Bl/6 (WT) and PI3Kγ−/− mice received VPA injections (30, 100 or 300 mg/kg, i.p.) and 30 min after they were submitted to the forced swimming (FS), tail suspension (TS) and open field (OF) tests. Another group was pretreated with rapamycin (5 mg/kg, i.p.) 150 min before VPA administration. Akt phosphorylation levels were measured by Western blotting.In WT mice, VPA (30 mg/kg) reduced the immobility time in both FS and TS tests. However, VPA (300 mg/kg) increased the immobility time in FS test. All doses of VPA did not alter locomotor activity. In PI3Kγ−/− mice, none of the doses revealed antidepressant-like effect. However, in the OF test, the lower dose of VPA increased the travelled distance in comparison with vehicle group. An increase in Akt phosphorylation levels was observed in WT, but not in PI3Kγ−/− mice. Finally, the pretreatment of WT mice with rapamycin abolished the antidepressant-like effect of VPA (30 mg/kg) in FS test.These data suggest that the antidepressant-like effects of VPA might depend on PI3K and mTOR activation. Thus, more studies are necessary to investigate the mechanisms involved in the antidepressant-like effect induced by VPA in order to investigate novel therapeutic targets for the treatment of depression.VPA revealed antidepressant-like effect in FS and TS tests in mice.VPA increased hippocampal phospho-Akt levels in WT, but not in PI3Kγ−/− mice.The antidepressant-like effect of VPA was not observed in PI3Kγ−/− mice.Rapamycin, a mTOR inhibitor, blocked the VPA antidepressant-like effect in FS test.