Running title : Modulation of supraspinal fatigue Conflicts of interest and source of funding: M. Klass: has no conflicts of interest, received a grant of the Fonds National de la Recherche Scientifique (FRS-FNRS; FC82578) for this study and has no professional relationships with companies or manufacturers B. Roelands: has no conflicts of interest, was supported by the Fund for Scientific Research Flanders (FWO) for this study and has no professional relationships with companies or

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... 2 M. Lévénez: has no conflicts of interest, did not receive external funding for this study and has no professional relationships with companies or manufacturers V. Fontenelle: has no conflicts of interest, did not receive external funding for this study and has no professional relationships with companies or manufacturers N. Pattyn: has no conflicts of interest, did not receive external funding for this study and has no professional relationships with companies or manufacturers R. Meeusen: has no conflicts of interest, did not receive external funding for this study and has no professional relationships with companies or manufacturers J. Duchateau: has no conflicts of interest, did not receive external funding for this study and has no professional relationships with companies or manufacturers 3 ABSTRACT Purpose: Prolonged exhaustive exercise induces a failure of the nervous system to activate the involved muscles maximally (i.e. central fatigue). Part of central fatigue may reflect insufficient output from the motor cortex (i.e. supraspinal fatigue), but the cause is unresolved. To investigate the potential link between supraspinal fatigue and changes in brain concentration of dopamine and noradrenaline in temperate environment, we combined neurophysiogical methods and pharmacological manipulation of these two neurotransmitters. Methods: Changes in performance of a cycling exercise (time trial; TT) were tested after oral administration of placebo, dopamine or noradrenaline reuptake inhibitors (methylphenidate and reboxetine, respectively) in well-trained male subjects. Changes in voluntary activation, corticospinal excitability and muscle contractile properties were tested in the knee extensors using transcranial magnetic stimulation and motor nerve electrical stimulation before and after exercise. A psychomotor vigilance task (PVT) was also performed. Results: Compared with placebo, methylphenidate did not affect exercise performance (P=0.19), but more time was needed to complete the TT after administration of reboxetine (~9%; P<0.05). For the latter condition, the reduced performance was accompanied by a central/supraspinal fatigue (5-6%; P<0.05) and worsened PVT performance (7%; P<0.05). For the three conditions, corticospinal excitability was unchanged, and peripheral fatigue was similar. Since the ingestion of reboxetine induced a greater decrease in voluntary activation and PVT performance after the TT than placebo, with no modification in corticospinal excitability, the noradrenaline reuptake inhibitor likely affected supraspinal circuits located prior to the motor cortex. Conclusion: These results suggest that noradrenaline, but not dopamine reuptake inhibition, contributes to the development of central/supraspinal fatigue after a prolonged cycling exercise performed in temperate conditions. 4