title: Serotonin as a Mediator of Fatigue During Exercise and Training
Creators: name: Dwyer, Dan
Publisher: name: Griffith University
Year: 2004
Subjects: subject: serotonin
subject: exercise
subject: fatigue
subject: rat
subject: rats
subject: brain
subject: receptor
subject: receptors
subject: neuromuscular function

description: Exercise has been shown to cause an increase in the concentration of brain serotonin (5-hydroxytryptamine, 5-HT) in humans and experimental animals. The increase in brain serotonin coincides with the onset of fatigue and is referred to as "central fatigue". Experiments in humans and animals involving serotonin receptor agonists have demonstrated reductions in exercise performance by simulating the exercise-induced increase in endogenous serotonin. Conversely, the administration of serotonin receptor antagonists has been shown to extend exercise performance in experimental animals, but not in humans. Although the relationship between the concentration of brain serotonin and exercise performance is well described in the literature, the precise effect of central fatigue on muscle function per se is unclear. Furthermore, there appear to be differences in serotonergic function between trained and untrained cohorts. However, it is not clear whether the differences are due to a training adaptation or if the differences are inherent in the individual. In addition, the time course of these adaptations and the mechanisms of adaptation are not known. The initial purpose of this thesis was to determine whether six weeks of endurance exercise training had any effect on central serotonin receptor sensitivity in Wistar rats. The rats ran on a treadmill 4 times per week with 2 exercise tests of endurance performance per week. Receptor sensitivity was determined indirectly, at the end of each training week, by the reduction in endurance performance, under the influence of a 5-HT1a agonist, (m-Chlorophenylpiperazine, m-CPP). Improved tolerance to the fatiguing effects of the serotonin agonist would suggest desensitisation of central serotonin receptors, probably 5-HT1a receptors. Two groups of controls were used to examine, i) the effect of the injection per se on exercise performance and ii) changes in serotonin receptor sensitivity associated with maturation, in the absence of any exercise training. In the training group, undrugged exercise performance significantly improved by 47% after 6 weeks of training (mean ± SEM, 4518 ± 729 s vs. 6640 ± 903 s, p=0.01). Drugged exercise performance also increased significantly from week 1 to week 6 (306 ± 69 s to 712 ± 192 s, p=0.004). Control group results indicated that the dose of m-CPP alone caused fatigue during exercise tests and that maturation was not responsible for any decrease in receptor sensitivity. Endurance training appears to stimulate an adaptive response to the fatiguing effects of increased brain serotonin, which may enhance endurance exercise performance. The purpose of the second set of experiments described in this thesis was to investigate changes in serotonin receptor sensitivity in response to exercise training in human subjects. Twelve male volunteers completed 30 minutes of stationary cycling at 70% of VO2peak, on 3 days per week, for 9 weeks. Serotonin receptor sensitivity was assessed indirectly by measuring the prolactin response to a serotonin receptor agonist (buspirone hydrochloride), using a placebo controlled, blind cross-over design. A sedentary group of control subjects were also recruited to control for possible seasonal variations in serotonin receptor sensitivity. Endurance capacity was also assessed as time to exhaustion while cycling at 60% of VO2peak. The exercise training caused a significant increase in aerobic power (VO2peak, 3.1±0.16 to 3.6±0.15 L.m-1, p&lt; 0.05) and endurance capacity (93±8 to 168±11 min, p&lt;0.05), but there was no change (p&gt;0.05) in the prolactin response to a serotonin agonist. However, 25% of the subjects in the training group demonstrated a decrease in receptor sensitivity, as indicated by a decrease in prolactin response. These results suggest that while the exercise training caused an increase in aerobic power and endurance capacity, there was no measurable change in 5-HT receptor sensitivity. In addition, it is possible that changes in receptor sensitivity may take longer to occur, the training stimulus used in the present investigation was inadequate or that changes occurred in other 5-HT receptor subtypes that were not assessed by the present methodology. The third set of experiments described here, investigated the changes in neuromuscular function under the influence of a serotonin receptor agonist (buspirone hydrochloride). Subjects were administered the agonist or a placebo in a blind cross over design. Measures of neuromuscular function included reaction time (RT), hand eye coordination (HEC), isometric neuromuscular control (INC), maximal voluntary isometric contractile force (MVIC-F), isometric muscular endurance capacity (IMEC) and various electromyographic (EMG) indices of fatigue in biceps brachii. A preliminary experiment was conducted to determine a drug dose that did not cause sedation of the research subjects. The agonist caused a significant (p&lt;0.05) decrease in MVIC-F, INC and IMEC. There was a non significant (p = 0.08) decrease in EMG amplitude during the MVIC-F trial with the agonist, compared to the effect of the placebo. The median EMG frequency during the IMEC test was also significantly less with the agonist, when compared to the placebo effect. There was a decline in RT and HEC, although this was not significant. These findings indicate that a serotonin receptor agonist causes a decrease in neuromuscular function during isometric muscle contractions. The decrements in muscle function reported in this study may help to explain previous reports of an association between increased brain serotonin concentration and a reduction in endurance performance. Although the present study does not exclude the possibility that an increase in brain serotonin does cause fatigue by affecting organs peripheral to the brain, it provides evidence of fatigue within the central nervous system. Further examination of the effect of a serotonin agonist on muscle function during non-isometric muscle contractions is warranted.