Objective:This study examined the influence of sigma-1 receptor (σ1R) knockout on affective behaviors. Methods:We employed 5-month-old σ1R knockout (σ1R-KO) mice. Depression-like behaviors were evaluated through open-field test (OFT),tail suspension test (TST),forced swimming test (FST) and Y-maze task. Results:In comparison with male wide-type (WT) mice,male σ1R-KO mice spent less time in the center field of OFT,and had longer immobility time in FST and TST. Furthermore,the male σ1R-KO mice spent less time in the novel arm than the known arm in Y-maze. By contrast,no difference in depression-like behaviors was found between female WT mice and σ1R-KO mice. In addition,the serum levels of estrogen in female KO mice and testosterone in male KO mice were not altered compared to WT mice. Conclusion:The σ1R-KO induced depression-like behaviors were male mice-specific,and maybe related with the antidepressant effect of estrogen.