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Eighteen healthy adults (9 males and 9 females; mean age\u00a0=\u00a023.4\u00a0\u00b1\u00a02.2\u00a0years) completed three experimental conditions. Participants ingested methylphenidate (MPH; 20\u00a0mg; primarily enhancing DA signaling), reboxetine (REB; 8\u00a0mg; selectively enhancing NA signaling), or placebo (10\u00a0mg lactose) prior to performing dynamic leg extensions until exhaustion. Behavioral, subjective, and physiological responses were assessed to evaluate drug\u2010specific effects using (generalized) linear mixed\u2010effects models. The fatiguing task effectively induced exhaustion in all conditions, evidenced by increases in self\u2010reported fatigue and exertion, heart rate, and blood lactate levels. MPH did not significantly improve the number of leg extension repetitions (+3.1%,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.23) or perceived exertion ratings. Perceived performance and vigor increased, while sleepiness decreased\u00a0across 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 (\u221213.2%,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.001) 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\u2010extension exercise in males and females.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      <jats:bold>Trial Registration:<\/jats:bold>\n                      G095422N and identifier NCT05880342\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejsc.70119","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T07:27:28Z","timestamp":1769585248000},"source":"Crossref","is-referenced-by-count":2,"title":["Distinct Roles of Dopamine and Noradrenaline in Physical Fatigue"],"prefix":"10.1002","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2637-3510","authenticated-orcid":false,"given":"Y. Laurisa Arenales","family":"Arauz","sequence":"first","affiliation":[{"name":"Human Physiology and Sports Physiotherapy Research Group Faculty of Physical Education and Physiotherapy Vrije Universiteit Brussel  Ixelles Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Mali","sequence":"additional","affiliation":[{"name":"Human Physiology and Sports Physiotherapy Research Group Faculty of Physical Education and Physiotherapy Vrije Universiteit Brussel  Ixelles Belgium"},{"name":"Institute for Kinesiology Research Science and Research Centre Koper  Koper Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0117-8356","authenticated-orcid":false,"given":"Elke","family":"Lathouwers","sequence":"additional","affiliation":[{"name":"Human Physiology and Sports Physiotherapy Research Group Faculty of Physical Education and Physiotherapy Vrije Universiteit Brussel  Ixelles Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9802-8367","authenticated-orcid":false,"given":"Jelle","family":"Habay","sequence":"additional","affiliation":[{"name":"Human Physiology and Sports Physiotherapy Research Group Faculty of Physical Education and Physiotherapy Vrije Universiteit Brussel  Ixelles Belgium"},{"name":"Research Foundation Flanders (FWO)  Brussels Belgium"},{"name":"LIFE Department Vital Signs and Performance Monitoring Research Unit Royal Military Academy  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0778-769X","authenticated-orcid":false,"given":"Leonardo de Sousa","family":"Fortes","sequence":"additional","affiliation":[{"name":"Graduate Program in Sport Sciences Federal University of Minas Gerais  Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7553-9957","authenticated-orcid":false,"given":"Romain","family":"Meeusen","sequence":"additional","affiliation":[{"name":"Human Physiology and Sports Physiotherapy Research Group Faculty of Physical Education and Physiotherapy Vrije Universiteit Brussel  Ixelles Belgium"},{"name":"BruBotics Vrije Universiteit Brussel  Brussels Belgium"},{"name":"Department of Sports, Recreation, Exercise and Sciences Faculty of Community and Health Sciences University of the Western Cape  Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7420-2137","authenticated-orcid":false,"given":"Uros","family":"Marusic","sequence":"additional","affiliation":[{"name":"Institute for Kinesiology Research Science and Research Centre Koper  Koper Slovenia"},{"name":"Department of Health Sciences Alma Mater Europaea University  Maribor Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6901-7199","authenticated-orcid":false,"given":"Kevin","family":"De Pauw","sequence":"additional","affiliation":[{"name":"Human Physiology and Sports Physiotherapy Research Group Faculty of Physical Education and Physiotherapy Vrije Universiteit Brussel  Ixelles Belgium"},{"name":"BruBotics Vrije Universiteit Brussel  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2808-044X","authenticated-orcid":false,"given":"Bart","family":"Roelands","sequence":"additional","affiliation":[{"name":"Human Physiology and Sports Physiotherapy Research Group Faculty of Physical Education and Physiotherapy Vrije Universiteit Brussel  Ixelles Belgium"},{"name":"BruBotics Vrije Universiteit Brussel  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2011.01.027"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2010.06.023"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00421\u2010019\u201004264\u2010w"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.e7586"},{"key":"e_1_2_13_6_1","unstructured":"CH Harmonised Guideline:Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2).2016. 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