ABSTRACTKetamine, an N-methyl-D-aspartate receptor antagonist, produces rapid antidepressant effects in patients with treatment-resistant depression. However, owing to the undesirable adverse effects of ketamine, there is an urgent need for developing safer and more effective prophylactic and therapeutic interventions for depression. Preclinical studies have demonstrated that activation of the mechanistic target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex (mPFC) mediates the rapid antidepressant effects of ketamine. The steroidal alkaloid tomatidine and its glycoside α-tomatine (tomatine) can activate mTORC1 signaling in peripheral tissues/cells. We examined whether tomatidine and tomatine exerted prophylactic and therapeutic antidepressant-like actions via mPFC mTORC1 activation using a mouse model of lipopolysaccharide (LPS)-induced depression. Male mice were intraperitoneally (i.p.) administered tomatidine/tomatine before and after the LPS challenge to test their prophylactic and therapeutic effects, respectively. LPS-induced depression-like behaviors in the tail suspension test (TST) and forced swim test (FST) were significantly reversed by prophylactic and therapeutic tomatidine/tomatine administration. LPS-induced anhedonia in the female urine sniffing test was reversed by prophylactic, but not therapeutic, injection of tomatidine, and by prophylactic and therapeutic administration of tomatine. Intra-mPFC infusion of rapamycin, an mTORC1 inhibitor, blocked the prophylactic and therapeutic antidepressant-like effects of tomatidine/tomatine in TST and FST. Moreover, both tomatidine and tomatine produced antidepressant-like effects in ovariectomized female mice, a model of menopause-associated depression. These results indicate that tomatidine and tomatine exert prophylactic and therapeutic antidepressant-like effects via mTORC1 activation in the mPFC and suggest these compounds as promising candidates for novel prophylactic and therapeutic agents for depression.