We have recently demonstrated that infusion of eicosapentaenoic acid-derived resolvin E1 (RvE1; 50 pg/side) into the medial prefrontal cortex (mPFC) exerts antidepressant effect in a murine lipopolysaccharide (LPS)-induced depression model. In the present study, we examined the roles of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and their downstream mTORC1 in the antidepressant actions of intra-mPFC RvE1 infusion in LPS-induced depression model mice using the tail suspension and forced swim tests. The results demonstrate that the antidepressant effects of intra-mPFC RvE1 infusion are completely blocked by co-infusion of a BDNF neutralizing antibody (nAb), a VEGF nAb or an mTORC1 inhibitor rapamycin. We also demonstrate that the antidepressant effects of intra-mPFC BDNF or VEGF infusion are blocked by co-infusion of rapamycin. Together, the current results indicate that BDNF/VEGF release and subsequent activation of mTORC1 in the mPFC are required for the antidepressant actions of RvE1.