BACKGROUND Avicularin (AL, quercetin-3-alpha-l-arabinofuranoside), a glycoside of quercetin, has been reported to display diverse pharmacological properties. The present study aimed to investigate whether AL has an anti-depressant-like effect on a mouse model of depression induced by chronic unpredictable mild stress (CUMS). MATERIAL AND METHODS A mouse model of depression was established and treated with different concentrations of AL (1.25, 2.5 or 5.0 mg/kg/d) and fluoxetine (20 mg/kg/d). Then, behavioral tests - sucrose preference test (SPT), forced swimming test (FST), and the tail suspension test (TST) - were performed. The levels proinflammatory cytokines - interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-alpha (TNF-alpha) - in the hippocampi of mice were detected by enzyme-linked immunosorbent assay (ELISA). Apoptosis of hippocampal neuronal cells was determined using flow cytometry. Expression levels of phosphorylated (p)-MEK1/2, p-ERK1/2, p-NF-kappaB (p-p65), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), Caspase3, and B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax) were measured by Western blot assay or/and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. RESULTS The results showed that AL significantly relieved CUMSinduced depressive-like behaviors. Compared with the model mice, AL treatment significantly increased the sucrose preference of the mice, and the immobility time in the FST and the TST were shortened. We also found that AL decreased CUMS-induced increases in the levels of IL-1ß, IL-6, and TNF-alpha in the hippocampi of mice. AL significantly decreased the apoptosis rate of hippocampal neuronal cells in mice, which was increased by CUMS. Furthermore, activation of the MEK/ERK/NF-kappaB pathway induced by CUMS was inhibited by AL treatment. CONCLUSIONS Our results show the anti-depressant-like effects of AL on CUMS-induced depression in a mouse model.