Sex-specific effects of chronic fluoxetine on c-Fos expression in Murine brain regions

Fluoxetine (FLX), a selective serotonin reuptake inhibitor, is widely prescribed for treating mood disorders. Despite its therapeutic benefits, the precise mechanisms and brain regions impacted by long-term FLX treatment remain understood. To explore this, we analyzed c-Fos immunoreactivity in brain regions associated with emotional regulation after 30-day oral FLX treatment in male and female mice. Our findings showed a significant reduction in c-Fos expression in FLX-treated groups compared to controls, suggesting decreased cellular activity in several brain regions. Furthermore, significant sex differences were observed as male mice exhibited higher c-Fos activity than females. Treatment interaction indicated FLX might reduce these sex disparities, except in the CA2 region of the hippocampus, where males maintained higher activity. Notably, FLX appeared to minimize the sex-based disparities in c-Fos expression in several regions, suggesting that FLX equalizes cellular activity across sexes in areas associated with cognitive and emotional functions. Altogether, these data indicate that FLX modulates cellular activity via a sex-dependent mechanism, which highlights the relevance of considering sex differences in the assessment of the neurobiological effects of FLX.