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Background Although thought as a multimodal-acting antidepressant targeting at the serotonin system, more and more other molecules are being reported to participate in the antidepressant mechanism of vortioxetine. A previous report has shown that vortioxetine administration enhanced the expression of rapamycin complex 1 (mTORC1) in neurons. It has been well demonstrated that mTORC1 participates in not only the pathogenesis of depression but also the pharmacological mechanisms of many antidepressants. Therefore, we speculate that the antidepressant mechanism of vortioxetine may require mTORC1. Methods Two mice models of depression (chronic social defeat stress and chronic unpredictable mild stress) and western blotting were first used together to examine whether vortioxetine administration produced reversal effects against the chronic stress-induced down-regulation in the whole mTORC1 signaling cascade in both the hippocampus and medial prefrontal cortex. Then, LY294002, U0126, and rapamycin were used together to explore whether the antidepressant effects of vortioxetine in mice models of depression were attenuated by pharmacological blockade of the mTORC1 system. Furthermore, LV-mTORC1-shRNA-EGFP was adopted to examine if genetic blockade of mTORC1 also abolished the antidepressant actions of vortioxetine in mice. Results Vortioxetine administration produced significant reversal effects against the chronic stress-induced down-regulation in the whole mTORC1 signaling cascade in both the hippocampus and medial prefrontal cortex. Both pharmacological and genetic blockade of the mTORC1 system notably attenuated the antidepressant effects of vortioxetine in mice. Conclusions Activation of the mTORC1 system in the hippocampus and medial prefrontal cortex is required for the antidepressant actions of vortioxetine in mice.