We have already reported that ovariectomized (OVX) rats reduced spontaneous activity and serotonin release levels of the amygdala in the dark term (B.B.R. 227(1)1-6(2012)). In this study, we examined whether sertraline as a SSRI recovered a spontaneous activity on OVX induced despair-like behaviors mice. The female ICR mice of 9-week old were received ovariectomy or sham operation. Sertraline (10 mg/kg/day, s.c.) or saline were administered to each groups for 8 weeks (6 times/week) starting from 8 weeks after OVX. The spontaneous activity of the mice was evaluated by using an activity sensor at dark term (19:00-7:00). Moreover, RNA expression levels of tryptophan hydroxylase (TPH) and XBP-1 were measured in hippocampus and prefrontal cortex by Real-time PCR. In the result, we revealed that these OVX induced despair-like behaviors were improved by administration of sertraline. In result of RT-PCR, sertraline significantly suppressed down-regulation of TPH expression level in hippocampus induced by OVX. In addition, sertraline significantly suppressed up-regulation of XBP-1 expression level in hippocampus induced by OVX. These results suggested that sertraline could improve the decrease in spontaneous activity mediated by serotonin level in hippocampus by the OVX.