Atractylenolide I (AT‑I), a major component of the rhizoma of Atractylodes macrocephala Koidz., exerts a wide range of activities. The purpose of the present study was to investigate the anti‑depressant‑like effect of AT‑I in a mouse model of chronic unpredictable mild stress (CUMS), and to explore the possible molecular mechanism involved. It was revealed that AT‑I significantly ameliorated CUMS‑induced depressive‑like behaviors, as evidenced by increased sucrose preference as well as shortened immobility time in the forced swimming and the tail suspension test. In addition, AT‑I reduced CUMS‑induced decreases in the concentrations of serotonin and norepinephrine in the hippocampus. Furthermore, AT‑I inhibited the activation of the nucleotide binding and oligomerization domain‑like receptor family pyrin domain‑containing 3 (NLRP3) inflammasome as well as the concentration of the pro‑inflammatory cytokine interleukin (IL)‑1β in the hippocampi of mice subjected to CUMS. In conclusion, the results of the present study suggested that AT‑I exerts anti‑depressant‑like effects in a CUMS‑induced model of depression in mice, the molecular mechanism of which is associated with the inhibition of NLRP3 inflammasome activation to decrease IL‑1β production.

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