This study investigated the influence of aerobic capacity on the activation of the central serotonergic system and exercise fatigue in young men that ingested a selective serotonin reuptake inhibitor and were then subjected to moderate-intensity physical exercise. The maximal oxygen consumption of sixteen volunteers was measured during an incremental test. The volunteers were divided into two groups: subjects with higher (HAC) and lower (LAC) aerobic capacities. The volunteers were subjected to four experimental trials in which they ingested either placebo or paroxetine (10, 20 or 40 mg) and, 4.5 h later, cycled at 60% of their maximal power output until reaching fatigue. None of the three paroxetine doses influenced the total exercise time in the LAC group. However, for the HAC group, the time to fatigue in the 20 mg paroxetine condition was 15% less than that in the placebo condition (76.3 ± 5.1 min vs. 90.0 ± 7.9 min; p < 0.05). The time to fatigue was higher in the HAC group than in the LAC group for all treatments. Our results provide additional evidence that aerobic capacity modulates the activity of the serotonergic system. However, contrary to what would be expected considering previous reports, the activation of the serotonergic system in exercising subjects in the HAC group was not less than that in the LAC group.

• The physical performance of the higher aerobic capacity group after administration of 20 mg of paroxetine decreased relative to that after administration of the placebo, whereas the same dose of paroxetine had no effect in the lower aerobic capacity group.

• Our results provide additional evidence that aerobic capacity modulates the activity of the serotonergic system.

• Contrary to what would be expected considering previous reports, the present findings suggest that the activity of the serotonergic system during exercise is not attenuated in individuals with a higher aerobic capacity relative to those that have a lower aerobic capacity.

• A dose-dependent effect of paroxetine on physical performance was not observed in either group; for example, in the subjects with higher aerobic capacity, 40 mg of paroxetine did not enhance or even reproduce the ergolytic effect caused by 20 mg of paroxetine.

• None of the peripheral variables measured explain the reduced total exercise time after administration of 20 mg of paroxetine in the subjects with higher aerobic capacity.