Enhanced availability of serotonin increases activation of unfatigued muscle but exacerbates central fatigue during prolonged sustained contractions.

Brief stimulation of the raphe-spinal pathway in the turtle spinal cord releases serotonin (5-HT) onto motoneurones to enhance excitability. However, intense release of 5-HT via prolonged stimulation results in 5-HT spillover to the motoneurone axon initial segment to activate inhibitory 5-HT1A receptors, thus providing a potential spinal mechanism for exercise-induced central fatigue. We examined how increased extracellular concentrations of 5-HT affect the ability to perform brief, as well as sustained, maximal voluntary contractions (MVCs) in humans. Paroxetine was used to enhance 5-HT concentrations by reuptake inhibition, and three studies were performed. Study 1 (n = 14) revealed that 5-HT reuptake inhibition caused an ∼4% increase in elbow flexion MVC. However, when maximal contractions were sustained, time-to-task failure was reduced and self-perceived fatigue was higher with enhanced availability of 5-HT. Study 2 (n = 11) used twitch interpolation to reveal that 5-HT-based changes in motor performance had a neural basis. Enhanced 5-HT availability increased voluntary activation for the unfatigued biceps brachii and decreased voluntary activation of the biceps brachii by 2-5% following repeated maximal elbow flexions. The final study (n = 8) investigated whether altered motoneurone excitability may contribute to 5-HT changes in voluntary activation. F-waves of the abductor digiti minimi (ADM) were unaffected by paroxetine for unfatigued muscle and marginally affected following a brief 2-s MVC. However, F-wave area and persistence were significantly decreased following a prolonged 60-s MVC of the ADM. Overall, high serotonergic drive provides a spinal mechanism by which higher concentrations of 5-HT may contribute to central fatigue.