The role of putative brain serotonergic and dopaminergic modulators in central fatigue during exercise in health and disease

The primary purpose of the present experiments was to elucidate the role of putative brain serotonergic and dopaminergic modulators and indices (markers) in 'central fatigue' during exercise in health and disease, with a concurrent examination of metabolic, cardiovascular and perceptual responses. In experiments (EXPs) 1 and 2, the subjects underwent three main exercise trials. The first, following a pre-exercise high CHO meal (Control trial) and the remaining two after a pre-exercise high fat meal with (FC trial) and without (F trial) caffeine. The use of fat meals was employed to elevate circulating plasma free fatty acids (FFA) levels in an attempt to produce i) a similar muscle metabolic adjustment, and, ii) a parallel displacement of plasma Trp from albumin by plasma FFA and therefore similar brain serotonin (5-HT) manipulation in both F and FC trials. Differences on brain 5-HT and dopamine (DA) modulators and indices, exercise performance and perceptual (RPE), metabolic and cardiovascular responses could be examined by ingestion of caffeine. Thus, caffeine would differentiate between peripheral and central aspects affecting exercise fatigue and therefore the mechanism(s) associated with central fatigue could be evaluated. Modulators and indices of brain 5-HT and DA functions (i.e. plasma free and total tryptophan (Trp), tyrosine (Tyr), large neutral amino acids (LNAA), Trp:LNAA ratio, free-[Trp];[Tyr] ratio, Trp:Tyr ratio, and prolactin) and exercise performance were not different between the trials but RPE was reduced and metabolic/cardiovascular responses increased during exercise with caffeine. The aim of EXP 3 was to examine the effects of a creatine (Cr) supplementation on putative modulators and indices of brain 5-HT and DA function and on thermal stress during prolonged exercise in the heat. The Cr was used as a 'vehicle' to increase hydration and/or reduce thermal stress-induced increase in brain 5-HT function. Cr reduced thermoregulatory (e.g. sweat rate, rectal temperature and heart rate) and perceptual responses, plasma free-[Trp] (P = 0.001) and free-[Trp]:[Tyr] ratio (P = 0.001) and enhanced endurance performance in subjects classified as 'responders' to Cr. The aim of the fourth EXP was to elucidate the role of putative modulators (Trp, LNAA, Tyr) of central fatigue in CFS, to evaluate the association between these modulators with perceptual and metabolic responses in CFS patients and to compare their results to those of matched sedentary controls. Taken together, the results across studies imply that putative modulators of brain serotonergic and dopaminergic systems (and therefore brain 5-HT and DA function) play a key role in pre exercise central motivation and also in central fatigue process of well-trained humans during exercise in the heat (EXP 3) and in the exacerbated RPE, exercise intolerance and pathogenesis of CFS (EXP 4). However, under physiological conditions this central neural drive of fatigue associated with metabolic up-regulation of brain 5-HT does not affect exercise performance of well- trained humans (EXPs 1,2). The exact mechanism(s) therefore for the attenuation of RPE with caffeine is unlikely to be a brain 5-HT-mediated but most likely a DA- mediated effect. (Abstract shortened by ProQuest.)