Fluoxetine reduces physical activity and promotes adiposity in female mice

Approximately 20% of college students in the U.S. are prescribed antidepressant medications. Selective Serotonin Reuptake Inhibitors (SSRIs) are one of the most prescribed antidepressant medications, with fluoxetine (i.e., Prozac) being one of the most well-known. Previous literature has established some interesting yet inconclusive findings with SSRI use on exercise performance and skeletal muscle including enhanced fatigue and decreased muscle weight as well as altered substrate and mitochondrial metabolism. The purpose of this study was to evaluate the effects of oral administration of fluoxetine on physical activity in mice. In the study, 14-week-old male (n=16) and female (n=16) mice were housed in cages with running wheels. After two weeks of voluntary wheel running (WHL), male and female mice (n=8 each group) were randomly assigned to fluoxetine-treatment (FLX, 10-12 mg/kg/day dissolved in drinking water) or control (CON, water only) for an additional 4 weeks. Mice were evaluated on a weekly basis that included measurement of water intake, body mass, and wheel activity. A cohort of sedentary CON and FLX male (n=6-8 per group) and female (n=8-9 per group) mice were also included for comparison. At the end of 6 weeks, tissues were harvested and weighed, and blood was collected. At week 2 of WHL, females significantly out-performed males (66.5±4.2 vs. 27.3±4.5 km/wk). FLX significantly reduced running activity in females by week 4, which declined to ~50% of the running distance achieved by female CON at week 6. In contrast, FLX caused a significant reduction in running distance in male mice at weeks 5 and 6, which was ~36% lower compared to male CON. While average and peak velocities were higher in both female groups compared to males (p < 0.05), FLX did not significantly affect running velocity in either sex. In sedentary mice, FLX did not affect body mass but significantly increased adipose tissue mass in both males and females by ~40% and 50%, respectively. Adipose tissue mass remained significantly higher in female (~60%), but not male, WHL+FLX mice. Quadriceps mass was not affected by FLX in either sex with a tendency towards higher masses in both female WHL groups (p < 0.10). In summary, our data show that FLX impacts the physical activity of mice, specifically in females. Despite reduced total running distance, intensity, as assessed by running velocity, was not significantly altered. FLX promotes adiposity in sedentary male and female mice that is attenuated with wheel running only in male mice. Overall, these data highlight important sex differences in physical activity and adiposity with SSRI treatment. This work was funded by a Student Achievement in Research and Creativity grant and the Summer Fellows program at Ursinus College. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.