Fatigue during prolonged exercise can be caused by peripheral mechanisms or by a failure to transmit or sustain drive to the muscle by the central nervous system (18). The role of neurotransmitters on the outcome of performance and in particular on fatigue has drawn the attention of researchers concerning their possible role in increasing or decreasing performance and influencing the hormonal response to exercise. Recently, interest in this area has focused on hypotheses involving exercise-induced alterations in neurotransmitter function as possible explanations for central fatigue. Alterations in serotonin (5-HT), catecholamines, and acetylcholine have all been implicated as possible mediators of central fatigue during exercise (6,7,18). These neurotransmitters are known to play a role in arousal, mood, motivation, vigilance, anxiety, and reward mechanisms and could, therefore, if adversely affected, impair performance.
Several studies examined the effect of serotonergic manipulation on exercise performance in humans and animals (6,19,20,21,27,29). Drugs that block the reuptake of serotonin have been used to understand the link between fatigue, serotonin, and the hypothalamic-pituitary-adrenal (HPA) axis regulation during exercise. Some studies showed a decrease (5,27,29) in performance when supplementing with selective serotonin reuptake inhibitors (SSRI). However, we found that fluoxetine, a selective 5-HT reuptake inhibitor, did not affect performance in well-trained athletes during a 90-min time trial at 65% Wmax (21). Increases in extracellular noradrenaline (NA) concentrations instead appear to be associated with motivation and drive (22). Moreover, noradrenergic mechanisms are thought to be involved in the control of level of arousal, consciousness, and reward mechanisms (22) and could therefore play a role in the enhancement of performance.
To better understand the role of neurotransmitters on fatigue and in the regulation of the HPA axis, the purpose of the present study was to examine the effects of a noradrenergic reuptake inhibitor (NARI) (reboxetine 2 × 4 mg; REB) on exercise performance and on the hormonal response to exercise in well-trained athletes. REB is a new antidepressant drug with potent and selective inhibition of NA reuptake that presents a rapid onset of action (25,30). Acute doses have been shown to increase extracellular NA concentrations with no influence on striatal dopamine (25). We therefore hypothesize that despite the fact that the hormonal response to exercise will be influenced by the NARI, exercise performance will be unmodified.
Seven healthy well-trained male cyclists (age: 23 ± 1.7 yr, height: 182 ± 5.8 cm, weight: 73.5 ± 8.5 kg, V̇O2max: 73.5 ± 6.4 mL·kg−1·min−1, Wattmax: 376 ± 11.7 W) participated to the study. All subjects read and signed an informed-consent form. This informed-consent form and the experimental procedure were approved by the Research Council of the Vrije Universiteit Brussels. Subjects performed one maximal exercise test to exhaustion (to determine V̇O2max and maximal power output: Wmax) and two endurance tests (time trials) starting at 65% Wmax. To exclude possible influences of prior exercise on the experimental treatment, the subjects were requested to avoid any intense or long-lasting physical exercise in the 2 d preceding each experiment. Standard preexercise meals were imposed the day before and the morning of the experiments.
Maximal exercise test.
In all tests, the subjects exercised on a cycle ergometer (Excalibur Lode, Groningen, The Netherlands). After resting measurements were collected, the maximal exercise test began with an initial workload of 3 min pedaling (70–80 RPM) at 50 W. Thereafter, the workload was increased by 50 W at 3-min stages until the subject was unable to maintain the set power output. V̇O2 was measured throughout the test via an automated system (Metamax, Cortex Biophysik GmbH, Leipzig, Germany). Only subjects with V̇O2max values greater than 50 mL kg−1 min−1 were considered for further experimentation.
Subjects performed two time trials separated by at least 1 wk to allow washout of the drug (8). The trials were performed in a double-blind, randomized, placebo-controlled, and cross-over design. The night before and the morning of the time trials, subjects ingested two capsules containing either placebo (PLAC) or 4 mg reboxetine (REB). All tests were performed at the same time of the day. After a short warm-up (5 min 100 W) subjects were asked to perform a certain amount of work (equal to about 90 min or 5400 s cycling at 65% Wmax) as described previously (21). The measure of performance was the time necessary to complete the target amount of work. This target amount of work is based on the maximal workload (ranging from 338 to 413 W) and calculated as follows: target amount of work (J) = 0.65 × Wmax × 5400.
During the test, subjects were informed about the percentage of the total preset work that had already been performed. Subjects did not receive any information on workload, pedaling rate, time, and heart rate. However, they were able to increase or decrease workload according to their feelings following the instruction to complete the target amount of work as fast as possible. During exercise, the subjects were allowed to drink water ad libitum. Subjects were also requested to state their rate of perceived exertion (RPE) according to Borg’s scale (3).
The drug and the placebo were prepared in capsules with the same volume, color, and dimensions. The capsules had the same weight and contained either reboxetine (Edronax®, Pharmacia and Upjohn, Brussels, Belgium) or placebo (lactose).
Blood samples were collected via an indwelling venous catheter 30 min before the start of the performance test, at 30-min time intervals, at the end of the experiment (END) (when the target amount of work was reached) and after 5 min of recovery (REC); 20-μL blood samples only for lactate determination were taken at the hyperemized earlobe and assayed by ESAT 6660 lactate (Medingen GmbH). Plasma catecholamines were determined with HPLC EC (9).
Samples for adrenocorticotropin hormone (ACTH), β-endorphins (β-E), and catecholamines were collected in prefrozen 4.5-mL K3 EDTA Vacutainer tubes (Becton Dickinson’s Vacutainer System Europe, Belliver Industrial Estate, Plymouth, U.K.), immediately centrifuged at 3000 RPM (Minifuge 2, Heraeus, Germany) for 10 min and frozen at −20°C until further analysis. Samples for cortisol, growth hormone (GH), and prolactin (PRL) were collected in 9.5-mL Vacutainer serum tubes (Becton Dickinson) and kept at room temperature for 1 h before centrifuging at 3000 RPM (Minifuge 2) for 10 min. Samples were then assayed via radioimmunoassay (RIA) for ACTH and β-E (Nichols Institute Diagnostics, San Juan Capistrano, CA), PRL (ROCHE Diagnostics GmbH, Mannheim, Germany), GH (Pharmacia & Upjohn Diagnostics AB, Uppsala, Sweden), and cortisol (DiaSorin, Stillwater, MN).
All data are expressed as means ± SEM. Statistical evaluation of the time trial data was performed using a paired Student’s t-test, whereas statistical evaluation of hormonal and metabolic differences during exercise was performed using an ANOVA repeated measure design and a LSD-planned comparisons test for post hoc tests. Significance was set at P < 0.05 for all the performed tests.
All subjects completed all trials and showed no sign of discomfort due to reboxetine. Exercise performance, measured as the time to complete the target amount of work, did not differ between trials (REB: 97 min ± 3 min, PLAC: 92 min ± 1 min, P = 0.2).
RPE values from the Borg scale measured during exercise at 15-s time intervals showed no difference between trials. RPE measured at the end of exercise was not different between trials (REB: 8.1 ± 0.9, PLAC: 7.7 ± 1).
Lactate concentrations, taken at 15-min time intervals, did not differ between trials at all time points. HR at rest (70 ± 4 bpm REB vs 61 ± 4.7 bpm PLAC) and during exercise did not differ between trials (HRmax: 177 ± 9.5 bpm REB vs 177 ± 8.6 bpm PLAC) (Table 1).
ACTH, cortisol, NA, PRL, and β-E concentrations increased significantly during exercise both in the placebo and in the REB trials (Fig. 1). GH increased significantly from rest to the first 30 min of exercise and thereafter decreased in the REB trial. For ACTH, β-E, PRL, cortisol, and NA, the concentrations at the end of exercise were significantly higher than the resting values, both in the PLAC and in the REB trials. These resting hormonal concentrations were never different between the two trials. Only GH concentrations were significantly higher at rest in the REB trial. At the end of exercise and during recovery, β-E and ACTH concentrations were significantly higher in the REB trial. PRL concentrations were significantly higher in the REB trial at minute 60 and end of exercise and during recovery. GH concentrations were statistically significantly higher at rest in the REB versus the PLAC trial and thereafter were significantly lower than the PLAC trial at minute 60 and end of exercise and during recovery. NA plasma concentrations were higher in the REB trial only during recovery, whereas no difference was observed in the adrenaline plasma concentrations.
The results of the present study demonstrate that performance is not improved by a noradrenergic reuptake inhibitor taken acutely at a dose of 8 mg. We actually found a trend toward a decrease in performance (longer time to complete the time trial) with REB supplementation. This was an unexpected result because, although the difference was statistically nonsignificant, 5 min for well-trained athletes is able to determine a victory during competition. To our knowledge, no study is available in literature that looks at the effects of REB or other NARI on exercise performance and on peripheral hormonal concentrations. The role of neurotransmitters on exercise performance and in particular on fatigue is controversial. The “central fatigue hypothesis” evolves around the exercise induced alterations in neurotransmitter function as a possible explanation for the early onset of fatigue during exercise. In particular, increases in 5-HT or a depletion in catecholamines during exercise have been considered responsible for the early onset of fatigue (6,7). Results concerning the effects of an increased extracellular 5-HT concentration on exercise performance are discordant. Selective serotonin reuptake inhibitors (SSRI) have been shown to decrease (5,27,29) or have no effect (21) on performance. However, the different hormonal response to exercise found with fluoxetine indicates a central effect of the drug and an interaction between neurotransmitters in regulating the HPA axis during exercise (21). Due to its well-known role on motor behavior and motivation, dopamine (DA) was the first neurotransmitter linked to CNS fatigue during exercise (7). In one of our previous studies (20), performance was not influenced by a DA precursor. Another catecholamine, NA, is related to increased motivation and drive (22) and therefore related to an enhancing effect on exercise performance and delaying fatigue. The present results demonstrate that during a time trial, performance is not influenced by a selective NARI in well-trained endurance athletes. However, the differences in the hormonal concentrations observed between the placebo and the REB trial indicate that the dose administered (2 × 4 mg) was sufficient in producing an acute central effect. It has been demonstrated in rats that a challenge dose of REB (15 mg·kg−1) is able to increase extracellular NA concentrations in the dorsal hippocampus and the frontal cortex (25). Subjects did not suffer from side effects in accordance with previous studies that showed that REB is well tolerated by patients with major depression at fixed doses up to 10 mg·d−1. The full therapeutic daily dose is normally 8 mg·d−1 (4).
ACTH, β-E, and PRL were significantly increased at the end of exercise and during recovery, whereas GH showed very high resting values and lower plasma concentrations during exercise in the REB trial versus the placebo trial. To increase NA extracellular content, REB has been shown to work not only by inhibiting the reuptake of NA but also via antagonism of the presynaptic α-2 receptors or by desensitization of the β-adrenoceptor density (12,15). Desensitization of the β-adrenoceptor density is evident only after 5 d of treatment and most probably not involved in the regulation of the observed hormonal response during exercise (24). In the present study, supplementation was given acutely; therefore, the differences observed in the hormonal response to exercise could be attributed to the inhibition of the NA reuptake alone, therefore to the higher extracellular NA concentrations. It is clear that more research on animals needs to be performed.
The noradrenergic control of PRL and β-E release is still unclear. However, in the present study, both are significantly higher during exercise in the REB trial. Similarly, tyrosine supplementation (the precursor of catecholamines) has been shown to increase PRL concentrations in trained athletes (27) as well as α-2 antagonists (16). ACTH concentrations increased due to REB supplementation. ACTH has previously been shown to be regulated by the presynaptic α-2 receptors via a glucocorticoid-sensitive mechanism (14). Yohimbine, an α-2 adrenergic receptor blocker is a potent stimulator of the ACTH secretion in the rat (1,10,11,13,28), whereas clonidine, an α-2 adrenergic receptor agonist, has been shown to inhibit pituitary ACTH release (26). REB has been shown to work via antagonism of the presynaptic α-2 receptors (12,15); therefore, it is possible that this is the regulating mechanism of ACTH response during exercise in the REB trial (for review see 2). Cortisol and adrenaline concentrations did not differ in the present study due to REB.
GH response to exercise in the REB trial was peculiar. Very high baseline values were followed by an inability of exercise to further increase GH concentrations; they gradually decreased and at the end of exercise were similar to resting values. The high GH resting values observed in the present study were most probably due to a noradrenergic effect (17). The decrease in GH concentrations during exercise can be explained by the fact that GH has been shown to autoinhibit its own release (23).
Lactate and HR were not influenced by the drug in the present study. Apparently, the drug has limited peripheral effects and is selective for a central action. Moreover, there were no subjects who reported or presented any side effects of the drug, before, during, or after the experiment. This again could be interpreted as a selectivity of action of the drug on central mechanisms.
In conclusion, within the limits of this experimental design, we were not able to show that exercise performance was influenced by a noradrenergic reuptake inhibitor, although the general impression was that with REB the time trial performance was slower. The hormonal modifications observed indicate that the drug had a central effect and that the hormones could have been modulated via an increase in NA extracellular concentrations due to the reuptake inhibition. Therefore, the “central component” of fatigue cannot be causally linked to the increase or decrease of one neurotransmitter. Further research is necessary to explore this complex interaction between neurotransmitters during exercise.
This research was supported by the Research Council of the Vrije Universiteit Brussel OZR 387-1999.
Address for correspondence: Prof. Dr. Romain Meeusen, Department of Human Physiology and Sportsmedicine, Vrije Universiteit Brussel Pleinlaan 2, 1050 Brussels, Belgium; E-mail: rmeeusen@ vub.ac.be.
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