Distinct Roles of Dopamine and Noradrenaline in Physical Fatigue

This triple-blinded randomized crossover study investigated the roles of dopamine (DA) and noradrenaline (NA) in regulating exercise performance and fatigue using acute pharmacological manipulation. Eighteen healthy adults (9 males and 9 females; mean age = 23.4 ± 2.2 years) completed three experimental conditions. Participants ingested methylphenidate (MPH; 20 mg; primarily enhancing DA signaling), reboxetine (REB; 8 mg; selectively enhancing NA signaling), or placebo (10 mg lactose) prior to performing dynamic leg extensions until exhaustion. Behavioral, subjective, and physiological responses were assessed to evaluate drug-specific effects using (generalized) linear mixed-effects models. The fatiguing task effectively induced exhaustion in all conditions, evidenced by increases in self-reported fatigue and exertion, heart rate, and blood lactate levels. MPH did not significantly improve the number of leg extension repetitions (+3.1%, p = 0.23) or perceived exertion ratings. Perceived performance and vigor increased, while sleepiness decreased across pretask and posttask assessments. Posttask temporal demand and overall task load were also reduced. In contrast, REB significantly reduced the number of leg extension repetitions (−13.2%, p < 0.001) without altering perceived exertion, mood, or performance perception. These findings show that DA and NA systems differently affect fatigue regulation. DA mainly influences cognitive and perceptual aspects, improving alertness and mood without significantly enhancing physical performance. In contrast, NA reduced physical performance without altering fatigue perception, indicating a dissociation between subjective fatigue and actual capacity. This study provides new evidence on how DA and NA shape both performance and perception during fatiguing leg-extension exercise in males and females. Trial Registration: G095422N and identifier NCT05880342.