Objective To investigate the effect of fluoxetine(FLX)in allivating depressive-like behaviors in chronic unpredictable mild stress(CUMS)rats through regulation of phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/AKT/mTOR)signaling pathway.Methods Twenty-four rats were randomly divided into four groups according to random number table method:Con group(healthy rats),CUMS group(CUMS-induced depressive rat model),FLX group(CUMS-induced depressive rat model intraperitoneally injected with 10 mg/kg FLX),and LY294002 group(CUMS-induced depressive rat model intraperitoneally injected with 0.002 μg/kg LY294002),with six rats in each group.The rats were exposed to a chronic unpredictable stress(CUS)environ-ment to establish depressive model.Behavioral indicators of rats in each group were observed and recorded,including sucrose preference test,immobility duration in the tail suspension test,and the immobility time in the forced swimming test.The levels of adrenocorticotropic hormone(ACTH),cortisol(CORT),interleukin(IL)-1β,IL-6,and tumor necrosis factor-α(TNF-α)in the serum of rats in each group were detected.The content of brain-derived neurotrophic factor(BDNF)in the hippocampal tissue was detected by immunohistochemistry.The expression levels of related proteins in the PI3K/AKT/mTOR signaling pathway were detected by Western blotting.Results Compared with the Con group,the CUMS group showed a decreased sucrose preference rate,BDNF level,p-PI3K/PI3K,p-AKT/AKT,and p-mTOR/mTOR,as well as prolonged immobility duration in the tail suspension test,prolonged immobility time in the forced swimming test,and increased levels of ACTH,CORT,IL-1β,IL-6,and TNF-α(P＜0.05).Compared with the CUMS group,the FLX group exhibited an increased sucrose preference rate,BDNF level,p-PI3K/PI3K,p-AKT/AKT,and p-mTOR/mTOR,as well as shortened immobility duration in the tail suspension test,shortened immobility time in the forced swimming test,and decreased levels of ACTH,CORT,IL-1 β,IL-6,and TNF-α,with statistically significant differences(P＜0.05).Compared with the FLX group,the LY294002 group showed a decreased sucrose preference rate,BDNF level,p-PI3K/PI3K,p-AKT/AKT,and p-mTOR/mTOR,as well as prolonged immobility duration in the tail suspension test,prolonged immobility time in the forced swimming test,and increased levels of ACTH,CORT,IL-1β,IL-6,and TNF-α,with statistically significant differences(P＜0.05).Conclusion FLX can regulate the secretion of ACTH,CORT,and BDNF,inhibit neuroinflammation,and improve depres-sive-like behaviors in CUMS rats,possibly by activating the PI3K/AKT/mTOR signaling pathway.