central nervous system fatigue central nervous system fatigue central nervous system fatigue, or central fatigue, is a form of fatigue that is associated with changes in the synaptic concentration of neurotransmitters within the central nervous system (cns; including the brain and spinal cord) which affects exercise performance and muscle function and cannot be explained by peripheral factors that affect muscle function. in healthy individuals, central fatigue can occur from prolonged exercise and is associated with neurochemical changes in the brain, involving (but not limited to) serotonin (5-ht), noradrenaline, and dopamine. the roles of dopamine, noradrenaline, and serotonin in cns fatigue is unclear, as pharmacological manipulation of these systems has yields mixed results. central fatigue plays an important role in endurance sports and also highlights the importance of proper nutrition in endurance athletes. neurochemical mechanisms existing experimental methods have provided enough evidence to suggest that variations in synaptic serotonin, noradrenaline, and dopamine are significant drivers of central nervous system fatigue. an increased synaptic dopamine concentration in the cns is strongly ergogenic (promotes exercise performance). paradoxically however, direct dopamine agonists such as bromocriptine and pramipexole have cause opposite, pro-fatigue effects in healthy humans. noradrenaline