Although monoamine-based pharmacological drugs revolutionized the treatment of major depressive disorder, about one third of patients experience treatment-resistant depression. Thus, development of antidepressant with novel mechanism is required. In this study, we investigated the involvement of microsomal prostaglandin E synthase-1 (mPGES-1), a terminal inducible enzyme for PGE₂ synthesis, in acute restraint stress (RS: 6 hr) and social defeat stress (SDS: 1 day). mPGES-1 mRNA was significantly increased after RS. Induction of mPGES-1 protein was observed in neurons in the frontal cortex (FC). PGE₂ in FC was also significantly upregulated in wild-type (WT) mice, but not in mPGES-1 knockout (ES1KO) mice. The inflammatory responses, such as increases in GFAP and TNF-α, observed after RS in ES1KO were significantly less than those in WT. After RS, there were no significant differences between WT and ES1KO in open field test (OFT), forced swimming test, elevated plus maze test (EPM) and marble burying test. On the other hand, in sucrose preference test, the ratio of sucrose intake after RS in WT was significantly less than that in ES1KO. In acute SDS model, social avoidance behavior was significantly observed after SDS. At the same time, upregulation of mPGES-1 was also observed in FC, amygdala and ventral tegmental area. Taken together, these results suggest that mPGES-1 is induced by acute stress in FC, and then contributes to brain inflammation and anhedonia through PGE₂ production. Thus, mPGSE-1 may be a promising novel therapeutic target for depression.