[Frontiers in Bioscience E2, 779-792, January 1, 2010]
CNS fatigue provoked by prolonged exercise in the heat
Section of Human Physiology, Department of Exercise and Sport Sciences, University of Copenhagen, Universitetsparken 13, DK-2100 Copenhagen O, Denmark
TABLE OF CONTENTS
1. ABSTRACT
Exercise-induced hyperthermia is associated with central fatigue as indicated by an impaired ability to sustain maximal motor activation during prolonged voluntary efforts. Therefore, exercise in hot environments challenges not only to the cardiorespiratory and locomotive systems but also to the brain. However, exercise with superimposed hyperthermia is not only a challenge to the brain it also provides an excellent model for studying factors of importance for central fatigue. Excessive heat storage within the brain appears to be the primary cause for the central fatigue during exercise in the heat, but pharmacological manipulations provide evidence for involvement of the dopaminergic system and other monoamines. Thus, enhanced dopaminergic activity may counteract hyperthermia mediated central fatigue and improve performance in the heat, while noradrenaline re-uptake inhibition appears to aggravate central fatigue and degrade exercise performance. Hyperthermia mediated central fatigue may include other cerebral perturbations such as reduced perfusion of the brain, accumulation of ammonia or depletion of neuronal energy stores, but further research is needed to elucidate their possible contributions.
2. INTRODUCTION
Fatigue emerges as an exercise-induced impairment of the ability to produce force and power or alternatively as an increased difficulty in sustaining a required pace or power output. Factors of both peripheral and central origin may influence fatigue and the relative importance of a given factor may to depend on the exercise mode, exercise intensity, duration and environmental settings (75; 87). The issue of hyperthermia-induced fatigue becomes relevant when exercise is conducted in environmental surroundings where endogenous heat production surpasses the capacity for heat release to the environment or markedly elevates the skin temperature and augments the core temperature response. During exercise in temperate climates, the body core temperature will increase by 1-2 ˚C depending on the exercise mode and intensity (86; 115). Also, the skin temperature remains low and persons most likely become fatigued for reasons unrelated to changes in body temperatures (1; 41; 46). In contrast during exercise with severe heat stress, a high body temperature may either directly or indirectly become the dominating factor. Some of the homeostatic disturbances that influences fatigue during normothermic exercise may still be of importance during exercise in the heat and interact with factors that are arising as direct effects of hyperthermia. Furthermore, the physiological mechanisms responsible for the development of hyperthermia-induced fatigue may include a variety homeostatic changes that arises in parallel with the increase in the body core temperature. However, these factors may be roughly divided into A) changes in the central nervous system (CNS) that leads to so-called central fatigue (38; 87; 94) and B) impairments of cardiovascular function that will reduce arterial oxygen delivery and subsequently deteriorate aerobic energy turnover within the exercising muscles and provoke peripheral fatigue (51; 60; 91). Factors related to A) Seems to be important mainly during prolonged exercise with a low to moderate intensity (40-70% of VO2max) conducted in very hot (from ~ 35 ˚C or above) or moderate hot environments with high humidity that will hamper the capacity for evaporative heat release or exercise in static air that will affect convective cooling. These combinations of environmental and endogenous (exercise-induced) heat stress may cause severe hyperthermia and elevate the temperatures of the body core and the brain to more than 40˚C (55; 83; 94; 112; 128). In contrast B) becomes relevant during high intensity exercise (close to VO2max). Across the specified exercise intensities, fatigue is likely a hybrid of both peripheral and central mechanisms, with the relative contribution depending on the specific exercise situation.
As mentioned above, fatigue arising with hyperthermia may interact with the fatigue that develops during normothermic exercise, e.g. depletion of muscle substrates or accumulation of muscle metabolites. However, during submaximal exercise in the heat, muscle glycogen stores are far from depleted at the point of exhaustion. Although, depletion of muscle glycogen may occur at localised sites around myofilaments, in single fibres or in connection with the sarcoplasmatic reticulum, the glycogen levels that are observed following exhaustive exercise with hyperthermia does not support that glycogen depletion is an important issue (39; 84). In addition, during submaximal exercise hyperthermia does not appear to cause a change in muscle metabolism from aerobic to anaerobic energy turnover that may explain the fatigue that arises during such exercise (50). Therefore, pH changes that subsequently may affect the cross-bridge cycle, or disturb potassium or calcium homeostasis seem to be of minor importance during submaximal exercise in the heat (84; 100).
Accordingly, plasma potassium, muscle and blood lactate levels are much lower than the levels observed during exhaustive maximal exercise or following submaximal exercise with hypoxia (53; 107).
The present review will focus on the CNS aspect of hyperthermia-induced fatigue, while the reader is referred to recent reviews (54; 89) for discussion of point B) i.e. hyperthermia-induced impairment in oxygen delivery to the exercising muscles which becomes relevant only during high intensity exercise. As indicated above, the oxygen delivery aspect is not relevant during prolonged submaximal exercise in the heat. When dehydration is prevented or remains below ~2%, cardiac output is either similar or only slightly reduced (52) and the perfusion of the exercising muscles is not reduced (84). Even when dehydration is superimposed and leg blood flow becomes reduced during submaximal cycling exercise in the heat (50), increased oxygen extraction (a-v DO2) by the exercising muscles is adequate to maintain muscle VO2 and avoid major changes in the metabolism (53). Therefore, during submaximal exercise below ~70% of VO2max the development of hyperthermia does not lead to metabolic disturbances of the myocellular homeostasis that are likely to impair muscle function. Furthermore, there is no evidence that exercise-induced hyperthermia in itself will hamper the contractile function of the skeletal muscles, at least within the temperature limits observed in healthy subjects (~ 40˚C in trained subjects exercising to exhaustion, but with individual body core temperatures up to ~ 41˚C and muscle temperatures that are 0.5-1˚C higher (55; 94)). Accordingly, Nielsen et al. (83) observed that force production during brief maximal voluntary contractions (MVC; ~ 2 sec duration) were unchanged for both exercised and "non-exercised" muscle groups following prolonged exercise in the heat that elevated the core temperature to ~ 40˚C and exhausted the trained subject after ~ 1 hour of exercise. Passive heating studies also indicate that high muscle temperatures does not deteriorate the contractile function (8; 80; 124) and it seems clear that hyperthermia-induced fatigue is not directly related to a reduced capacity of the skeletal muscles to produce force. Yet, during a sustained contraction the ability to maintain voluntary force production for more than a few seconds seems to be markedly impaired by hyperthermia (94), and this could also influence motor performance during dynamic exercise and affect the development of fatigue during prolonged exercise.
3. THE EVIDENCE FOR CNS FATIGUE
Already in the past century, several authors speculated that exhaustion during prolonged exercise in the heat could relate to central fatigue rather than being related to the cardiovascular stress that arises with hyperthermia (17; 69; 83). However, there was no direct measurement that supported their assumptions and the hypothesis relied on so called circumstantial evidence; i.e. absence of peripheral fatigue and failure to observe increased levels of muscle metabolites that could explain the marked reductions in performance. The influence of central fatigue is still debated; however, several studies have recently provided experimental evidence for central fatigue either as consequence of exercise-induced hyperthermia or following passive hyperthermia. Maximal isometric contractions combined with superimposed electrical nerve or muscle stimulation or transcranial magnetic stimulation of the motor cortex are the commonly applied models to investigate the contribution of central vs. peripheral fatigue, but some studies have also investigated the issue during isokinetic contractions (46; 47). The results presented in Figure 1 are from the first experimental study that utilized this approach to demonstrate that hyperthermia reduces voluntary activation during a sustained maximal knee extension (94). In this study maximal isometric contractions were preceded by bicycle exercise at 60% of VO2max either with or without superimposed environmental heat stress. Exercise in the heat increased the core temperature to ~ 40�C and exhausted the subjects after 50 min of exercise, whereas during the control trial the core temperature plateaued at ~ 38�C and exercise was maintained for 1 h without exhausting the subjects. Although the hyperthermic exercise trial exhausted the subjects, it did not impair the ability of the knee extensors to generate force when electrical stimulation was superimposed, and voluntary force production was similar during the initial phase of the MVC. However, in the hyperthermic trial the subjects were unable to sustain the same activation, as during the control trial, and the voluntary force production as well as the rectified integrated surface electromyogram (EMG) from m. vastus lateralis became low.
In addition, following a resembling cycle ergometer protocol, force development during a sustained handgrip contraction followed a similar pattern of response as for the knee extensors, indicating that the attenuated ability to activate the skeletal muscles did not depend on whether the muscle group had been active or inactive during the preceding exercise bout (94). Conversely, hyperthermia did not affect maximal force development or central activation during brief maximal knee extensions (2 s duration) even if the MVCs were repeated 40 times and interspaced by only 3 s of recovery (94). This indicate that although hyperthermia provokes central fatigue, the CNS regains the ability to activate the skeletal muscles within a short period of recovery (94).
Also, when the effect of hyperthermia is compared with that of hypoglycemia on the development of fatigue during prolonged exercise and the activation pattern during a sustained MVC (cf ref# (88; 94), it appears that both conditions cause central fatigue. However, during hyperthermia as well as during hypoglycemia voluntary force production may be maintained for a brief period of time, whereas central activation becomes low if the contraction is sustained for more than some seconds. Depletion of substrates and metabolic disturbances within the CNS and/or alterations in the release or synaptic levels of certain neurotransmitters are potential mechanisms underlying the decline in central activation (87; 117). However, sensory feedback from the contracting muscles could also be a major factor influencing the pattern of CNS activation. Inhibitory feedback from muscle chemo- and metaboreceptors may be of minor importance for the activation level during the initial phase of isometric contractions, whereas it may inhibit motor activation when the contraction is sustained and muscle metabolites accumulate (5; 66). It also needs to be considered that heating will cause a decrease in time to peak twitch force as well as a reduction in the half-relaxation time of the skeletal muscles and therefore hyperthermia may increase the firing frequency necessary to sustain maximal activation of the motor units. During a prolonged MVC the fatigue arising during hyperthermia may represent a failure of descending voluntary drive to compensate for changed muscle properties, despite the availability of additional cortical output (80; 124). Once again this signifies that fatigue is rarely determined by a single factor but may be influenced by a number of physiological changes. In relation to the reduced force production during prolonged MVCs, it appears that central activation becomes markedly impaired when hyperthermia is combined with inhibitory signals from the skeletal muscles, whereas inhibition from a high brain/hypothalamus temperature (23) may be overridden, at least for a brief period, providing inhibitory feedback from chemo- and metaboreceptors is low.
3.1. Dynamic exercise
During dynamic exercise it becomes much more difficult to obtain direct evidence for central fatigue. Several studies observed that both mammalians and humans seem to terminate voluntary exercise at a certain core temperature (28; 45; 55; 127) - there may be differences in the tolerable temperature between species and there is also variation between subjects. In humans, factors such as, motivation, exercise mode and especially training, acclimatization and hydration status may explain part of these inter-individual differences. But for a given individual in a standardized situation, exercise seems to be terminated with remarkable little variation in the end-point core temperature (45; 55; 69; 83; 127). The experiments by Caputa et al. (23) where brain and body core temperatures in exercising goats were separately manipulated (by changing the temperatures of implanted thermo elements) indicate that the main reason why exercise is terminated or the exercise intensity becomes markedly reduced is the high hypothalamic temperature. Thus, elevating the hypothalamic temperature independently of the temperature of the remaining of the body core reduced the goats' ability and willingness to continue exercise. It is therefore hypothesized that inhibitory signals arising in hypothalamus as consequence of an excessive increase in the temperature of the brain will either directly or indirectly hamper motor activity (94; 99). Also, in humans it seems clear that the impairments in voluntary muscle activation is related to elevations of the core temperature rather than to changes in skin or the local muscle temperature (123). A high skin temperature may indirectly influence the brain by increasing the cardiovascular stress and in turn this may impair orthostatic tolerance and reduce the cerebral blood flow ((132; 133) - see later section for discussion of cerebral blood flow). However, the elevated muscle or a high skin temperature in itself seems to have little influence on the reduction in voluntary muscle activation (123).
It has been proposed that the end-point core and brain temperature is "critical" and represents a definitive safety break against catastrophic heat injury (69; 83), as supported by the observation, that trained subjects during repeated trials with different starting temperatures or rates of heat storage stop exercising at similar body core temperatures of ~ 40° C, but after dissimilar exercise durations (45; 55; 83). However, the consistency of the core temperatures at voluntary exhaustion in laboratory experiments both in trained (55) and untrained subjects (28) may relate to the usual study designs in these types of experiments, where low to moderate intensity exercise is combined with a large external (sometimes uncompensable) heat stress. Accordingly, other factors that may influence fatigue become of minor importance under such conditions, whereas the progressive inhibition of motor activation that arises simultaneously with the rise in brain/hypothalamic temperature becomes the dominant factor dictating the point of exhaustion. However, the body core temperature at exhaustion may be influenced by factors such as training status, exercise intensity/mode and motivation. E.g. differences in motivation between laboratory experiments and sports competitions combined with the influence of the subjects personality and training status could explain why untrained subjects during hot exercise conditions become exhausted at core temperatures between 38 and 39�C (116). Whereas trained subjects may attain core temperatures as high as 41�C during sports competitions (104), although they as described above become exhausted, or unwilling to continue exercising, when their core temperature exceeds ~ 40�C in a laboratory setting (55; 83; 94). Also, pharmacological alterations of synaptic dopamine levels (112; 128) or caffeine administration (Nybo et al., unpublished observations) may elevate the end-point temperature and hyperthermia-induced central fatigue should not be considered as an all-or-none phenomenon that occurs only when the core and brain temperature reaches a critical point. Rather, there appears to be a progressive inhibition of the brain areas responsible for motor activation when the core temperature increases above the normothermic level and together with all the other factors that affects the CNS including feedback from the periphery it may provoke central fatigue (80; 87).
During exercise with constant power output, the central fatigue seems to emerge as a gradual increase in perceived exertion, and this is accompanied by a gradual slowing of the electroencephalogram as the core temperature increases above ~ 38˚C (96), while hyperthermia-induced fatigue will result in a reduction in power output during time trails (126; 128) and during exercise where subjects are instructed to adjust their power output to maintain a predefined perception of effort (125). Also, peak and average power output during repeated sprinting becomes reduced by hyperthermia (36) and it is noteworthy that the "performance pattern" during repeated sprinting resembles that observed for sustained isometric contractions (cf Figures 1 and 2), and that the impaired performance is accompanied by reduced and not enhanced accumulation of substances involved with peripheral fatigue such as plasma K+, H+, and muscle lactate (36). This indicates that fatigue during repeated sprints is not caused by inadequate oxygen delivery or disturbances of muscle homeostasis, but rather by the direct temperature influence on the CNS. Although, the evidence for central fatigue during repeated sprinting and prolonged work is circumstantial (36; 44; 65; 96; 103), it seem likely that hyperthermia through some of the same mechanisms that influenced voluntary motor activation during isometric contractions also may become of importance during ongoing dynamic exercise. In accordance, Martin et al. (70) report that exercise-induced hyperthermia also lowers voluntary drive to the skeletal muscles in an exercise protocol with frequently repeated maximal isokinetic contractions.
In regard to dynamic exercise and the capacity to produce power, an increased muscle temperature will increase the speed of the cross bridge cycle and, consequently, power output during a single sprint will increase (8). However, whole-body hyperthermia degrades the ability to sustain power output for prolonged periods and performance during repeated sprinting is also impaired by hyperthermia (Figure 2). Thus, force and power production appears to be unchanged or improved when the activation period is relatively short, while sustained or repeated efforts are hampered by the hyperthermia mediated reduction in CNS drive (36; 94). Although, the contractile function of the skeletal muscle is not impeded by hyperthermia per se (83; 94), the possibility that high temperatures have a detrimental effect on mitochondrial function is often mentioned referring to the work by Brooks et al. (20) and Willis et al. (131) since they reported a 20% reduction in the ADP/O ratio at 43° C when compared to that at 37° C. Therefore, they suggested that high muscle temperatures might compromise the properties of the inner mitochondrial membrane and cause a nonspecific proton leakage (20; 131). However, the transferability of the results from these in vitro measurements to in vivo situations is not clear. In humans exercising at submaximal work intensities no differences in oxygen consumption are observed over a wide range of core and muscle temperatures (~37° C to ~41° C) (55; 94), and it appears that hyperthermia-induced exhaustion in exercising humans occurs before mitochondrial respiration is perturbed and probably before other functions of the muscle cell are jeopardized. Accordingly, during acclimatization studies where subjects exercise to voluntary exhaustion and may attain core and muscle temperatures above 40˚C for ten consecutive days, they gradually improve performance (83; 85). This improvement would seem unlikely if the high body temperatures caused severe muscle damage or other permanent perturbations of peripheral or central cell functions. Also, this observation signifies that subjects normally terminate exercise (reach exhaustion) before their core and tissue temperatures become excessively high and causes persisting cell damage.
4. CNS FACTORS INFLUENCING FATIGUE
A factor that potentially could jeopardize CNS function and influence the development of fatigue during prolonged exercise with hyperthermia is the reduction in cerebral blood flow (CBF) that arises in parallel with the reduction in arterial carbon dioxide pressure (PaCO2). Hyperthermia is both at rest and during exercise associated with hyperventilation (95; 130), and during submaximal exercise this may lower the arterial carbon dioxide pressure and reduce the cerebral blood flow (92; 95). The global cerebral blood flow is to a large extend influenced by PaCO2 and since the cerebral CO2 reactivity (change in CBF for a given change in PaCO2) appears to increase during hyperthermia, blood flow to the brain may be reduced by up to 30% (see ref (92; 95; 106; 132) for details). However, at the same time as CBF declines the arterio-venous oxygen difference increases and the global cerebral metabolic rate for oxygen increases in spite of the reduced CBF. However, the combination of increased oxygen utilisation (most likely related to a Q10 effect on the cerebral metabolic rate; (22; 68)) and reduced perfusion will cause a reduction of the cerebral capillary oxygen level and the mitochondrial oxygen pressure may decline by ~ 5 mmHg (92; 98). Never the less, global lactate spill over from the brain remains low and unaltered during exercise with hyperthermia and at the present there is no experimental evidence or indications that inadequate oxygen delivery to the brain causes a change in the cerebral metabolism from aerobic to anaerobic metabolism or that the reduced perfusion is directly involved with the CNS fatigue that arises during prolonged exercise in the heat (92). However, a 5 mmHg decline in the average cerebral mitochondrial oxygen pressure is close to the critical level of reduction that may be tolerated by the brain without changes in the cerebral metabolism and deterioration of motor function (98; 105). It can therefore not be excluded that inadequate oxygen delivery to the brain becomes of importance during exercise with severe hyperthermia where subjects may push themselves beyond the limits that are observed during controlled laboratory experiments.
4.1. Influence from pharmacological or nutritional interventions
Several authors have proposed that exercise-induced alteration in the cerebral levels of serotonin (5-HT) and dopamine (DA) but also noradrenaline (NA), glutamate, GABA and acetylcholine may influence the development of fatigue (15; 33; 42; 42; 73; 75; 81; 87). Although, these theories have been supported by investigation in rodents (33; 59; 73) the experimental evidence from studies with either nutritional or pharmacological manipulations in exercising humans have until recently not been able to verify or refuse these theories. However, exercise with superimposed heat stress appears to be an excellent "fatigue model" for studying the potential involvement of different neurotransmitter systems or so-called "central fatigue hypotheses". During submaximal exercise in the heat exhaustion may be reached with little or no reduction in the contractile function of the skeletal muscles and since central factors rather than local peripheral fatigue dominates the development of fatigue, it also seems more likely that a significant performance effect will emerge if a given pharmacological or nutritional intervention plays a role for central fatigue. During the last couple of years numerous studies have utilised this approach to investigate and more convincingly provide experimental evidence for the importance and involvement of some of the neutransmitter systems.
4.2. Serotonergic activity
In the 1980ties Newsholme and co-workers (3; 81) proposed that tryptophan uptake by the brain would increase the cerebral levels of seretonin (5-hydroxytryptamine) and that this could provide a possible explanation for central fatigue during prolonged exercise. In short the hypothesis states that the serotonergic neurones may be affected when the plasma levels of branched-chain amino acids (BCAA) fall while the concentration of plasma fatty acid increases during prolonged exercise. The increased levels of fatty acids in plasma will cause a displacement of tryptophan from albumin and elevate the plasma level of free tryptophan. Therefore the concentration ratio between free tryptophan and BCAA may increase and enhance the cerebral uptake of tryptophan and cause an increased synthesis of 5-hydroxytryptamine in brain. The latter increases the activity of some serotonergic neurons in the brain which could influence arousal and increase the mental effort necessary to maintain athletic activity. Ingestion of BCAA should lower the cerebral uptake of tryptophan since they are transported via the same carrier system and according to the theory BCAA ingestion should therefore prevent central fatigue (75; 82). However, it appears that a significant uptake of tryptophan by the brain does not become relevant unless plasma fatty are markedly elevated (16; 87), while no tryptophan uptake is observed during 1 hour of exercise either with or without heat stress (97). In accordance, neither Cheuvront et al. (29) nor Watson et al. (129) observed any effect of branched-chain amino acid supplementation on the exercise capacity in hot environments. In contrast, Mittleman et al. (77) observed that branched-chain amino acid supplementation extended time to exhaustion in both men and women exercising in a warm environment (34˚C and 40% relative humidity). However, in that study the exercise intensity was quite low and the subjects were not hyperthermic by the end of the exercise trials (core temperatures below 38˚C), and exhaustion was probably related to other factors than hyperthermia-induced central fatigue. Thus, while the rationale for the ''tryptophan-serotonin-fatigue hypothesis'' is clear and although it is supported by results from animal studies, the experimental evidence from human studies indicate that the theory is not relevant for the central fatigue that arises during prolonged exercise with hyperthermia and its relevance during prolonged exercise at normal environmental temperatures is probably restricted to ultra endurance event conducted without carbohydrate supplementation (16; 97).
However, this must not be misinterpreted. Serotonergic neurones may indeed influence the development of fatigue and it may also influence other neurotransmitter systems of importance for fatigue e.g. dopaminergic neurones (75). But it appears that simple nutritional interventions or pharmacological manipulations with extracellular/synaptic serotonin levels are not sufficient to alter exercise performance in humans. In relation to the latter, results from studies with pharmacological manipulations should be interpreted with caution since different doses and the complex action of the drug employed may obscure the results. Thus, a recent study indicates that inhibition of serotonin reuptake may have a minor detrimental influence on performance during exercise in the heat (Roelands et al. unpublished).
4.3. Dopamine and Noradrenalin
It is well known that dopaminergic neurones play important roles during motor activation and that dopamine release from the substantia nigra is necessary for activation of the basal ganglia, a collection of midbrain neurons responsible for the initiation of movement (27; 43). Manipulations that attempt to increase dopamine synthesis (9; 31; 74; 118; 119) stimulate extracellular DA release (13; 14; 14; 19; 63), inhibit DA reuptake (9; 10), or directly activate DA neurons and/or DA receptors (21; 61) are some of the methods employed by researchers to prolong the increase in DA during exercise to fatigue (please see (42) for overview of the different pharmacological intervention studies that have been conducted in thermoneutral environments in humans and animals). Some of these manipulations have been successful in impacting exercise-induced fatigue with the use (and abuse) of amphetamine as the most potent drug (18; 25). Amphetamine is thought to exert its effect mainly through enhanced dopamine release; however, it may also influence other catecholaminergic neurons and inhibit the synthesis of serotonin (26; 42). The isolated effects of enhancing extracellular dopamine levels is therefore not clear and other strategies to directly affect dopaminergic activity or manipulate central catecholamine levels have failed to influence exercise capacity during exercise in temperate conditions (75; 76). E.g. administration of a dopamine precursor (L-DOPA (74)) or combined dopamine/norepinephrine reuptake inhibition with bupropion does not influence performance during prolonged exercise in thermoneutral environments (75; 101). Furthermore, neither a noradrenalin (reboxetine) nor a serotonin/noradrenalin (venlafaxine) reuptake inhibitor had any effect on performance during prolonged exercise in normal ambient temperature (101; 102). Despite a failure to influence performance, the neuroendocrine response in these studies suggested that the pharmacological manipulations indeed were able to affect the intended neurotransmitter systems.
However, a recent series of studies employing preloaded time trials (1 h of cycling at 55 % VO2max proceeded by 30 min time trial) have been carried out both in thermoneutral (18˚C) and hot (30˚C) environment and with this approach Meeusen and co-workers (110; 112; 128) have been able to observe significant performance effects of their pharmacological interventions. In the first of these studies (128), the subjects ingested a combined DA/NA reuptake inhibitor (bupropion) or placebo prior to the trials. In accordance with previous studies this had no effect in the thermoneutral environment (similar performance during placebo and bupropion trial in 18˚C) but DA/NA reuptake inhibition induced a 9% performance improvement during exercise in the heat (see Figure 3A). The increase in performance was accompanied by a higher heart rate and the attainment of significantly higher core temperature during the bupripion trial in the heat. Interestingly, this occurred without any change in the subjects' perceived exertion or thermal sensation. A similar, but more pronounced response was found after acute administration of a selective DA reuptake inhibitor (methylphenidate; (112)), which improved performance in the heat by 16% (Figure 3B). Exercise in the heat impaired time trial performance in both studies (compare pla18 and pla30 in Figures 3A and B), but selective DA or combined DA/NA reuptake inhibition seem to counteract some of the hyperthermia-induced fatigue. In contrast administration of a norepinephrine reuptake inhibitor (Reboxetine) prior to exercise decreases performance both in thermoneutral and hot environments (110). Taken together these studies elegantly demonstrate that enhanced dopaminergic activity induced by acute DA reuptake inhibition has a performance enhancing effect during exercise in the heat where performance seems to be largely influenced by central fatigue (89), whereas no effects of the reuptake inhibitors are observed during exercise at normal ambient temperatures, where central fatigue still may play a role, but where the relative influence from central factors seems to of less importance compared to the hyperthermic condition (94). In the above mentioned studies the reuptake inhibitors have been administrated on the day and/or evening prior to exercise. Interestingly, it seems that chronic administration of bupropion for consecutive days will cause adaptation of the central neurotransmitter homeostasis, resulting in a different response to the drug and eliminate the performance effect (111). At present, this difference between acute and chronic/repeated administration of bupropion is not clear, but it may relate to an up-regulation of the DA transporter in the caudate putamen and nucleus accumbens, causing an increase in DA reuptake (122).
In the studies by Meeusen and co-workers (112; 128), the acute performance effect of the DA reuptake inhibitors were confined to the hot trials, however, these experiments strengthen the idea that the dopaminergic system is involved in the aetiology of central fatigue during various types of strenuous exercise. Especially when the above findings are combined with the knowledge from previous studies with amphetamine (18; 134), which as discussed appear to be a more potent way to enhance DA activity and with a significant effect on performance and central fatigue during exercise in normal environmental temperatures. However, amphetamine is also a much more dangerous drug, and it should be mentioned that the combination of exercise in the heat and abuse of amphetamine or amphetamine-like drugs may have fatal consequences as it could cause excessive hyperthermia (67). Interpretation of results from studies with pharmacological manipulation should always be made with great caution, but the exercise model that combines exercise with hyperthermia with different pharmacological or nutritional treatments may in many ways be a good and sensitive approach for exploring factors involved with central fatigue.
4.4. Caffeine
The ergogenic effect of caffeine (1,3,7-trimethylxanthine) is well known (56; 57; 120; 121) and the influence of caffeine on endurance performance is most likely multifactorial (48; 49; 56; 64). There is evidence for a peripheral effect of caffeine on the excitation-contraction coupling of skeletal muscle (4), but the increase in exercise performance seen following intracerebroventrical caffeine injection in rats also provides strong evidence for a central ergogenic effect (32; 121). Since hyperthermia is associated with central fatigue it would seem straight forward to suggest that caffeine would improve performance during exercise in the heat. Furthermore, caffeine is a adenosine receptor antagonist that influences both adenosine A(1) and A(2A) receptors, and the modulation of dopamine transmission through A2A receptors has been implicated as one of the most important CNS effects of caffeine (12; 24). Adenosine A2A receptors have a unique cellular and regional distribution in the basal ganglia, being particularly concentrated in areas richly innervated by dopamine such as the caudate-putamen and the globus pallidus (24). Adenosine A2A receptors are located on striatopallidal neurons and are capable of forming functional heteromeric complexes with dopamine D2 receptors (79). Caffeine ingestion may therefore indirectly enhance dopaminergic activity in those brain areas and given the involvement of these areas in motor activation and the dopaminergic systems involvement in central fatigue and particularly hyperthermia-induced fatigue, it would be logical if caffeine improved exercise performance in the heat.
However, the effect of caffeine on performance in the heat is not clear. Del Coso et al. (34) observed that caffeine ingestion increased maximal cycling power measured during a 4 sec maximal effort performed every 30 min during 120 min of cycle exercise at ~60 % of VO2max and prevented the hyperthermia-induced decline in maximal voluntary activation that was observed following the submaximal exercise trials in the heat when no caffeine was ingested. This ergogenic effect was present both in trials with no fluid replacement and in trials where dehydration was prevented. In contrast, Cheuvront et al. (30) observed no effect of caffeine or ingestion of another nutritional adenosine inhibitor (quercetin) on time trial performance in the heat, and comparable findings have been reported previously (6; 113). In accordance with the results from Del Coso et al. (34) and supporting the idea that caffeine could counteract central fatigue, we have also observed that caffeine ingestion prior to exercise to exhaustion at a submaximal work load (60% of VO2max in a 40�C environment) may change the relationship between the rise in perceived exertion and the rise in the core temperature - so perceived exertion for a given core temperature becomes reduced when caffeine is ingested (Nybo et al. unpublished observations). Also, similarly to the observations with DA reuptake inhibition (112; 128) the subjects in our experiment were able to tolerate a higher core temperature at exhaustion when they ingested caffeine prior to the exercise trials. However, a significant performance effect was absent, because caffeine also induced a faster increase in the body core temperature (see references (6; 7; 10; 30; 35; 37) for a balanced and more detailed overview of the hydration and temperature effects of caffeine ingestion prior to or during exercise in the heat). Therefore, caffeine may have a beneficial effect in relation to counteracting the central fatigue that arises with hyperthermia, but this is offset because caffeine also has a thermogenic effect (11; 62; 114) that induces a more rapid core temperature elevation during some exercise conditions (30).
5. SUMMARY AND PERSPECTIVES
It is clear that an elevated core temperature impairs motor performance and that hyperthermia-induced fatigue involves perturbations of the brains ability to sustain sufficient activation of the skeletal muscles. The cerebral perfusion is reduced, but oxygen delivery to the brain does not appear to be critically low during laboratory experiments. Rather, the elevated brain temperature in itself seems to be the main factor affecting motor activation, but feedback from the skeletal muscles and dopaminergic activity are indeed also of importance. In humans the time course of how dopaminergic activity changes during prolonged exercise is at present not known and it remains speculative if the development of central fatigue relates to low or inadequate extracellular dopamine levels. However, counteracting central fatigue by pharmacological or nutritional intervention may have consequences. In the laboratory both untrained and trained subjects in general appear to terminate voluntary exercise before it jeopardizes cell function, but future experiments should try to elucidate if the attainment of core and brain temperatures above the "normal" level becomes critical and associated with symptoms of cellular stress. It is possible that heat acclimation and physical training may induce cellular adaptations which increase heat tolerance in various tissues (72) and this could explain why some subjects may endure temperature as high as 41�C while others terminate exercise with much lower core temperatures. In regard to the association between different neurotransmitter systems and the development of central fatigue the focus have mainly been on serotonin, dopamine and noradrenaline, however, other neurotransmitters such glutamate, acetylcholine, adenosine and GABA have been tentatively suggested to influence central fatigue (2; 32; 59). Furthermore, both inflammatory cytokines (interleukins such as IL-1 and Il-6; (40; 58; 75; 93; 108; 109)) and ammonia accumulation in the brain could be of importance (59; 78; 90). At present there are too few data to draw conclusions regarding their importance, but it may be useful to investigate their importance in a setup that involves exercise in the heat. Thus, exercise in the heat may on one hand side be a formidable challenge to the body and the brain (71), but it may also provide an excellent opportunity for studying factors involved with central fatigue.
6. ACKNOWLEDGEMENTS
Dr. Michael Sawka is greatly accredited for his comments and proofreading of the manuscript.
7. REFERENCES
1. Abbiss CR and Laursen PB. Models to explain fatigue during prolonged endurance cycling. Sports Med 35: 865-898, 2005.
doi:10.2165/00007256-200535100-00004
PMid:16180946
2. Abdelmalki A, Merino D, Bonneau D, Bigard A and Guezennec C. Administration of a GABAB agonist baclofen before running to exhaustion in the rat: effects on performance and on some indicators of fatigue. Int J Sports Med 18: 75-78, 1997.
doi:10.1055/s-2007-972598
PMid:9081260
3. Acworth I, Nicholass J, Morgan B and Newsholme EA. Effect of sustained exercise on concentrations of plasma aromatic and branched-chain amino acids and brain amines. Biochem Biophys Res Commun 137: 149-153, 1986.
doi:10.1016/0006-291X(86)91188-5
PMid:2424444
4. Allen DG and Westerblad H. The effects of caffeine on intracellular calcium, force and the rate of relaxation of mouse skeletal muscle. J Physiol 487 (Pt 2): 331-342, 1995.
5. Amann M, Eldridge MW, Lovering AT, Stickland MK, Pegelow DF and Dempsey JA. Arterial oxygenation influences central motor output and exercise performance via effects on peripheral locomotor muscle fatigue in humans. J Physiol 575: 937-952, 2006.
doi:10.1113/jphysiol.2006.113936
PMid:16793898 PMCid:1995675
6. Armstrong LE, Casa DJ, Maresh CM and Ganio MS. Caffeine, fluid-electrolyte balance, temperature regulation, and exercise-heat tolerance. Exerc Sport Sci Rev 35: 135-140, 2007.
doi:10.1097/jes.0b013e3180a02cc1
PMid:17620932
7. Armstrong LE, Pumerantz AC, Roti MW, Judelson DA, Watson G, Dias JC, Sokmen B, Casa DJ, Maresh CM, Lieberman H and Kellogg M. Fluid, electrolyte, and renal indices of hydration during 11 days of controlled caffeine consumption. Int J Sport Nutr Exerc Metab 15: 252-265, 2005.
8. Asmussen E and Bøje O. Body Temperature and Capacity for Work. Acta Physiol Scand 10: 1-22, 1945.
doi:10.1111/j.1748-1716.1945.tb00287.x
9. Avraham Y, Hao S, Mendelson S and Berry EM. Tyrosine improves appetite, cognition, and exercise tolerance in activity anorexia. Med Sci Sports Exerc 33: 2104-2110, 2001.
doi:10.1097/00005768-200112000-00020
10. Bell DG, Jacobs I, McLellan TM, Miyazaki M and Sabiston CM. Thermal regulation in the heat during exercise after caffeine and ephedrine ingestion. Aviat Space Environ Med 70: 583-588, 1999.
11. Belza A, Toubro S and Astrup A. The effect of caffeine, green tea and tyrosine on thermogenesis and energy intake. Eur J Clin Nutr 63: 57-64, 2009.
doi:10.1038/sj.ejcn.1602901
PMid:17882140
12. Ben-Jonathan N and Hnasko R. Dopamine as a prolactin (PRL) inhibitor. Endocr Rev 22: 724-763, 2001.
doi:10.1210/er.22.6.724
PMid:11739329
13. Bhagat B and Wheeler N. Effect of amphetamine on the swimming endurance of rats. Neuropharmacol 12: 711-713, 1973.
doi:10.1016/0028-3908(73)90124-X
PMid:4730378
14. Bhagat B and Wheeler N. Effect of nicotine on the swimming endurance of rats. Neuropharmacol 12: 1161-1165, 1973.
doi:10.1016/0028-3908(73)90073-7
PMid:4782695
15. Blomstrand E, Celsing F and Newsholme EA. Changes in plasma concentrations of aromatic and branch-chained amino acids during sustained exercise in man and their possible role in fatigue. Acta physiol Scand 133: 115-121, 1988.
doi:10.1111/j.1748-1716.1988.tb08388.x
PMid:3227900
16. Blomstrand E, Moller K, Secher NH and Nybo L. Effect of carbohydrate ingestion on brain exchange of amino acids during sustained exercise in human subjects. Acta physiol Scand 185: 203-209, 2005.
doi:10.1111/j.1365-201X.2005.01482.x
PMid:16218925
17. Booth J, Marino F and Ward JJ. Improved running performance in hot humid conditions following whole body precooling. Med Sci Sports exerc: 27: 943-949, 1997.
doi:10.1097/00005768-199707000-00014
18. Borg G, Edstrom CG, Linderholm H and Marklund G. Changes in physical performance induced by amphetamine and amobarbital. Psychopharmacol 26: 10-18, 1972.
doi:10.1007/BF00421914
PMid:5051458
19. Bracken RM, Linnane DM and Brooks S. Plasma catecholamine and nephrine responses to brief intermittent maximal intensity exercise. Amino Acids 36: 209-217, 2009.
doi:10.1007/s00726-008-0049-2
PMid:18297236
20. Brooks GA, Hittelman KJ, Faulkner JA and Beyer RE. Temperature, skeletal muscle mitochondrial functions and oxygen debt. Am J Physiol 220: 1053-1059, 1971.
21. Burgess ML, Davis JM, Borg TK and Buggy J. Intracranial self-stimulation motivates treadmill running in rats. J Appl Physiol 71: 1593-1597, 1991.
22. Busija DW, Leffler CW and Pourcyrous M. Hyperthermia increases cerebral metabolic rate and blood flow in neonatal pigs. Am J Physiol 255: H343-H346, 1988.
23. Caputa M, Feistkorn G and Jessen C. Effect of brain and trunk temperatures on exercise performance in goats. Pflugers Arch Physiol 406: 184-189, 1986.
doi:10.1007/BF00586681
PMid:3960700
24. Cauli O and Morelli M. Caffeine and the dopaminergic system. Behav Pharmacol 16: 63-77, 2005.
doi:10.1097/00008877-200503000-00001
PMid:15767841
25. Chandler JV and Blair SN. The effect of amphetamines on selected physiological components related to athletic success. Med Sci Sports Exerc 12: 65-69, 1980.
doi:10.1249/00005768-198021000-00013
26. Chaouloff F, Laude D and Merino D. Amphetamine and alfa-methyl-p-tyrosine affect the exercise induced imbalance between the availability of tryptophan and synthesis of serotonin in the brain of the rat. Neuropharmacol 26: 1099-1106, 1987.
doi:10.1016/0028-3908(87)90254-1
PMid:2443870
27. Chaudhuri A and Behan PO. Fatigue and basal ganglia. J Neurol Sci 179: 34-42, 2000.
doi:10.1016/S0022-510X(00)00411-1
PMid:11054483
28. Cheung SS and McLellan TM. Heat acclimation, aerobic fitness, and hydration effects on tolerance during uncompensable heat stress. J Appl Physiol 84: 1731-1739, 1998.
29. Cheuvront SN, Carter R, III, Kolka MA, Lieberman HR, Kellogg MD and Sawka MN. Branched-chain amino acid supplementation and human performance when hypohydrated in the heat. J Appl Physiol 97: 1275-1282, 2004.
doi:10.1152/japplphysiol.00357.2004
PMid:15358751
30. Cheuvront SN, Ely BR, Kenefick RW, Michniak-Kohn BB, Rood JC and Sawka MN. No effect of nutritional adenosine receptor antagonists on exercise performance in the heat. Am J Physiol 296: R394-R401, 2009.
31. Chinevere TD, Sawyer RD, Creer AR, Conlee RK and Parcell AC. Effects of L-tyrosine and carbohydrate ingestion on endurance exercise performance. J Appl Physiol 93: 1590-1597, 2002.
32. Davis JM, Zhao Z, Stock HS, Mehl KA, Buggy J and Hand GA. Central nervous system effects of caffeine and adenosine on fatigue. Am J Physiol Regul Integr Comp Physiol 284: 399-404, 2003.
33. Davis, J. M. and Bailey, S. P. Possible mechanisms of central nervous system fatigue during exercise. Med Sci Sports exerc 29: 45-57, 1997.
doi:10.1097/00005768-199701000-00008
34. Del Coso J, Estevez E and Mora-Rodriguez R. Caffeine effects on short-term performance during prolonged exercise in the heat. Med Sci Sports Exerc 40: 744-751, 2008.
doi:10.1249/MSS.0b013e3181621336
35. Del CJ, Estevez E and Mora-Rodriguez R. Caffeine during exercise in the heat: thermoregulation and fluid-electrolyte balance. Med Sci Sports Exerc 41: 164-173, 2009.
36. Drust B, Rasmussen P, Mohr M, Nielsen B and Nybo L. Elevations in core and muscle temperature impairs repeated sprint performance. Acta physiol Scand 183: 181-190, 2005.
doi:10.1111/j.1365-201X.2004.01390.x
PMid:15676059
37. Falk B, Burstein R, Rosenblum J, Shapiro Y, Zylber-Katz E and Bashan N. Effects of caffeine ingestion on body fluid balance and thermoregulation during exercise. Can J Physiol Pharmacol 68: 889-892, 1990.
38. Febbraio MA. Does muscle function and metabolism affect exercise performance in the heat? Exerc Sport Sci Rev 28: 171-176, 2000.
39. Febbraio MA, Snow RJ, Stathis CG, Hargreaves M and Carey MF. Effect of heat stress on muscle energy metabolism during exercise. J Appl Physiol 77: 2827-2831, 1994.
40. Febbraio M and Pedersen BK. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. Faseb Js 16: 1335-1347, 2002.
doi:10.1096/fj.01-0876rev
PMid:12205025
41. Fitts RH. Cellular mechanisms of muscle fatigue. Physiol Rev 74: 49-94, 1994.
42. Foley TE and Fleshner M. Neuroplasticity of dopamine circuits after exercise: implications for central fatigue. Neuromolecular Med 10: 67-80, 2008.
doi:10.1007/s12017-008-8032-3
PMid:18274707
43. Freed C and Yamamoto B. Regional brain dopamine metabolism: a marker for the speed, direction and posture of moving animals. Science 229: 62-65, 1985.
doi:10.1126/science.4012312
PMid:4012312
44. Fritzsche R, Switzer T, Hodgkinton B, Lee S, Martin JC and Coyle EF. Water and carbohydrate ingestion during prolonged exercise increase maximal neuromuscular power. J Appl Physiol 88: 730-737, 2000.
45. Fuller A, Carter RN and Mitchell D. Brain and abdominal temperatures at fatigue in rats exercising in the heat. J Appl Physiol 84: 877-883, 1998.
46. Gandevia SC. Spinal and Supraspinal Factors in Human Muscle Fatigue. Physiol Rev 81: 1725-1789, 2002.
47. Gandevia SC, Allen GM and McKenzie DK. Central fatigue - Critical Issues, Quatification and Practical Implications. In: Fatigue, edited by Gandevia SC, Enoka RM, McComas AJ, Stuart D and Thomas C. New York: Plenum Publishing Corporation, 1995.
48. Gandevia SC and Taylor JL. Supraspinal fatigue: the effects of caffeine on human muscle performance. J Appl Physiol 100: 1749-1750, 2006.
doi:10.1152/japplphysiol.00121.2006
PMid:16714410
49. Ganio MS, Klau JF, Casa DJ, Armstrong LE and Maresh CM. Effect of caffeine on sport-specific endurance performance: a systematic review. J Strength Cond Res 23: 315-324, 2009.
50. González-Alonso J, Calbet JA and Nielsen B. Muscle blood flow is reduced with dehydration during prolonged exercise in humans. J Physiol 513: 895-905, 1998.
doi:10.1111/j.1469-7793.1998.895ba.x
PMid:9824726 PMCid:2231307
51. González-Alonso J and Calbet J. Reductions in Systemic and Skeletal Muscle Blood Flow and Oxygen Delivery Limit Maximal Aerobic Capacity in Humans. Circulation 107: 824-830, 2003.
doi:10.1161/01.CIR.0000049746.29175.3F
PMid:12591751
52. González-Alonso J, Mora-Rodriguez JR and Coyle EF. Stroke volume during exercise: interaction of environment and hydration. Am J Physiol 278: H321-H330, 2000.
53. González-Alonso J, Calbet JA and Nielsen B. Metabolic and thermodynamic responses to dehydration-induced reductions in muscle blood flow in exercising humans. J Physiol 520: 577-589, 1999.
doi:10.1111/j.1469-7793.1999.00577.x
PMid:10523424 PMCid:2269598
54. Gonzalez-Alonso J, Crandall CG and Johnson JM. The cardiovascular challenge of exercising in the heat. J Physiol 586: 45-53, 2008.
doi:10.1113/jphysiol.2007.142158
PMid:17855754
55. Gonzalez-Alonso J, Teller C, Andersen S, Jensen F, Hyldig T and Nielsen B. Influence of body temperature on the development of fatique during prolonged exercise in the heat. J Appl Physiol 86: 1032-1039, 1999.
56. Graham TE. Caffeine and exercise: metabolism, endurance and performance. Sports Med 31: 785-807, 2001.
doi:10.2165/00007256-200131110-00002
PMid:11583104
57. Graham TE, Hibbert E and Sathasivam P. Metabolic and exercise endurance effects of coffee and caffeine ingestion. J Appl Physiol 85: 883-889, 1998.
58. Gray SR, Robinson M and Nimmo MA. Response of plasma IL-6 and its soluble receptors during submaximal exercise to fatigue in sedentary middle-aged men. Cell Stress Chaperones 13: 247-251, 2008.
doi:10.1007/s12192-008-0019-3
PMid:18320358 PMCid:2673892
59. Guezennec C, Abdelmalki A, Serrurier B, Merino D, Bigard X, Berthelot M, Pierard C and Peres M. Effects of prolonged exercise on brain ammonia and amino acids. Int J Sports Med 19: 323-327, 1998.
doi:10.1055/s-2007-971925
PMid:9721055
60. Hargreaves M and Febbraio MA. Limits to exercise performance in the heat. Int J Sports Med 19: 115-116, 1998.
doi:10.1055/s-2007-971973
PMid:9694414
61. Heyes MP, Garnett ES and Coates G. Central dopaminergic activity influences rats ability to exercise. Life Sci 36: 671-677, 1985.
doi:10.1016/0024-3205(85)90172-9
PMid:3918227
62. Hoffman JR, Kang J, Ratamess NA, Jennings PF, Mangine G and Faigenbaum AD. Thermogenic effect from nutritionally enriched coffee consumption. J Int Soc Sports Nutr 3: 35-41, 2006.
doi:10.1186/1550-2783-3-1-35
PMid:18500961 PMCid:2129151
63. Kalinski MI, Dluzen DE and Stadulis R. Methamphetamine produces subsequent reductions in running time to exhaustion in mice. Brain Res 921: 160-164, 2001.
doi:10.1016/S0006-8993(01)03113-4
PMid:11720722
64. Kalmar JM and Cafarelli E. Caffeine: A valuable tool to study central fatigue in humans? Exerc Sport Sci Rev 32: 143-147, 2004.
doi:10.1097/00003677-200410000-00004
PMid:15604932
65. Kay D, Marino F, Cannon J, St Clair Gibson A, Lambert M and Noakes T. Evidence for neuromuscular fatigue during high-intensity cycling in warm, humid conditions. Eur J Appl Physiol 84: 115-121, 2001.
doi:10.1007/s004210000340
PMid:11394239
66. Kent-Braun JA. Central and peripheral contributions to muscle fatigue in humans during sustained maximal effort. Eur J Appl Physiol 80: 57-63, 1999.
doi:10.1007/s004210050558
67. Kiyatkin EA. Brain hyperthermia during physiological and pathological conditions: causes, mechanisms, and functional implications. Curr Neurovasc Res 1: 77-90, 2004.
doi:10.2174/1567202043480233
PMid:16181068
68. Klementavicius R, Nemoto EM and Yonas H. The Q10 ratio for basal cerebral metabolic rate of oxygen in rats. J Neurosurg 85: 482-487, 1996.
doi:10.3171/jns.1996.85.3.0482
PMid:8751636
69. MacDougal JD, Reddan WG, Layton CR and Dempsey JA. Effects of metabolic hyperthermia on performance during heavy prolonged exercise. J Appl Physiol 36: 538-544, 1974.
70. Martin PG, Marino FE, Rattey J, Kay D and Cannon J. Reduced voluntary activation of human skeletal muscle during shortening and lengthening contractions in whole body hyperthermia. Exp Physiol 90: 225-236, 2005.
doi:10.1113/expphysiol.2004.028977
PMid:15604113
71. Maughan R and Shirreffs S. Exercise in the heat: challenges and opportunities. J Sports Sci 22: 917-927, 2004.
doi:10.1080/02640410400005909
PMid:15768725
72. McClung JP, Hasday JD, He JR, Montain SJ, Cheuvront SN, Sawka MN and Singh IS. Exercise-heat acclimation in humans alters baseline levels and ex vivo heat inducibility of HSP72 and HSP90 in peripheral blood mononuclear cells. Am J Physiol Regul Integr Comp Physiol 294: R185-R191, 2008.
doi:10.1152/ajpregu.00532.2007
73. Meeusen R and De Meirleir K. Exercise and Brain Neurotransmission. Sports Med 20: 160-188, 1995.
doi:10.2165/00007256-199520030-00004
PMid:8571000
74. Meeusen R, Roeykens J, Magnus L, Keizer H and De Meirleir K. Endurance performance in humans: The effect of a dopamine precursor or a specific serotonin (5-HT2A/2C) antagonist. Int J Sports Med 18: 571-577, 1997.
doi:10.1055/s-2007-972683
PMid:9443587
75. Meeusen R, Watson P, Hasegawa H, Roelands B and Piacentini MF. Central fatigue: the serotonin hypothesis and beyond. Sports Med 36: 881-909, 2006.
doi:10.2165/00007256-200636100-00006
PMid:17004850
76. Meeusen R, Watson P, Hasegawa H, Roelands B and Piacentini MF. Brain neurotransmitters in fatigue and overtraining. Appl Physiol Nutr Metab 32: 857-864, 2007.
doi:10.1139/H07-080
77. Mittleman K, Ricci M and Bailey S. Branched-chain amino acids prolong exercise during heat stress in men and women. Med Sci Sports Exerc 30: 83-91, 1998.
doi:10.1097/00005768-199801000-00012
78. Mohr M, Rasmussen P, Drust B, Nielsen B and Nybo L. Environmental heat stress, hyperammonemia and nucleotide metabolism during intermittent exercise. Eur J Appl Physiol 97: 89-95, 2006.
doi:10.1007/s00421-006-0152-6
PMid:16485104
79. Morelli M, Di PT, Wardas J, Calon F, Xiao D and Schwarzschild MA. Role of adenosine A2A receptors in parkinsonian motor impairment and l-DOPA-induced motor complications. Prog Neurobiol 83: 293-309, 2007.
doi:10.1016/j.pneurobio.2007.07.001
PMid:17826884
80. Morrison S, Sleivert GG and Cheung SS. Passive hyperthermia reduces voluntary activation and isometric force production. Eur J Appl Physiol 91: 729-736, 2004.
doi:10.1007/s00421-004-1063-z
PMid:15015001
81. Newsholme EA, Acworth I and Blomstrand E. Amino-Acids, brain neurotransmitters and a functional link between muscle and brain that is important in sustained exercise. In: Advances in Biochemistry, edited by Benzi G. London: John Libbey Eurotext Ltd., 1987.
82. Newsholme EA and Blomstrand E. Tryptophan, 5-hydroxytryptamine and a possible explanation for central fatigue. Adv Exp Med Biol 384: 315-320, 1995.
83. Nielsen B, Hales JRS, Strange NJ, Christensen NJ, Warberg J and Saltin B. Human circulatory and thermoregulatory adaptations with heat acclimation and exercise in a hot, dry environment. J Physiol 460: 467-485, 1993.
84. Nielsen B, Savard G, Richter EA, Hargreaves M and Saltin B. Muscle blood flow and metabolism during exercise and heat stress. J Appl Physiol 69: 1040-1046, 1990.
85. Nielsen B, Strange S, Christensen NJ, Warberg J and Saltin B. Acute and adaptive responses in human to exercise in a warm, humid environment. Pflugers Arch Physiol 434: 49-56, 1997.
doi:10.1007/s004240050361
PMid:9094255
86. Nielsen M. Die Regulation der Körpertemperatur bei muskelarbeit. Skand Arch Physiol 79: 193-230, 1938.
87. Nybo L and Secher NH. Cerebral perturbations provoked by prolonged exercise. Prog Neurobiol 72: 223-261, 2004.
doi:10.1016/j.pneurobio.2004.03.005
PMid:15142684
88. Nybo L. CNS fatigue and prolonged exercise: effect of glucose supplementation. Med Sci Sports Exerc 35: 589-594, 2003.
doi:10.1249/01.MSS.0000058433.85789.66
89. Nybo L. Hyperthermia and fatigue. J Appl Physiol 104: 871-878, 2008.
doi:10.1152/japplphysiol.00910.2007
PMid:17962572
90. Nybo L, Dalsgaard MK, Steensberg A, Moller K and Secher NH. Cerebral ammonia uptake and accumulation during prolonged exercise in humans. J Physiol 563: 285-290, 2005.
doi:10.1113/jphysiol.2004.075838
PMid:15611036
91. Nybo L, Jensen T, Nielsen B and Gonzalez-Alonso J. Effects of marked hyperthermia with and without dehydration on VO2 kinetics during intense exercise. J Appl Physiol 90: 1057-1064, 2001.
92. Nybo L, Møller K, Volianitis S, Nielsen B and Secher NH. Effects of hyperthermia on cerebral blood flow and metabolism during prolonged exercise in humans. J Appl Physiol 93: 58-64, 2002.
93. Nybo L, Nielsen B, Møller K, Pedersen BK and Secher NH. Interleukin-6 release from the human brain during prolonged exercise. J Physiol 542: 991-995, 2002.
doi:10.1113/jphysiol.2002.022285
PMid:12154196 PMCid:2290444
94. Nybo L and Nielsen B. Hyperthermia and central fatigue during prolonged exercise in humans. J Appl Physiol 91: 1055-1060, 2001.
95. Nybo L and Nielsen B. Middle cerebral artery blood flow velocity is reduced with hyperthermia during prolonged exercise in humans. J Physiol 534: 279-286, 2001.
doi:10.1111/j.1469-7793.2001.t01-1-00279.x
PMid:11433008 PMCid:2278686
96. Nybo L and Nielsen B. Perceived exertion during prolonged exercise with progressive hyperthermia is associated with an altered electrical activity of the brain. J Appl Physiol 91: 2017-2023, 2001.
97. Nybo L, Nielsen B, Blomstrand E, Moller K and Secher N. Neurohumoral responses during prolonged exercise in humans. J Appl Physiol 95: 1125-1131, 2003.
98. Nybo L and Rasmussen P. Inadequate Cerebral Oxygen Delivery and Central Fatigue during Strenuous Exercise. Exerc Sport Sci Rev 35: 110-118, 2007.
doi:10.1097/jes.0b013e3180a031ec
PMid:17620929
99. Nybo L, Secher NH and Nielsen B. Inadequate heat release from the human brain during prolonged exercise with hyperthermia. J Physiol 545: 697-704, 2002.
doi:10.1113/jphysiol.2002.030023
PMid:12456844 PMCid:2290690
100. Parkin JM, Carey MF and Febbraio MA. Effect of ambient temperature on human skeletal muscle metabolism during fatiguing submaximal exercise. J Appl Physiol 86: 902-908, 1999.
101. Piacentini MF, Meeusen R, Buyse L, De SG and De MK. Hormonal responses during prolonged exercise are influenced by a selective DA/NA reuptake inhibitor. Br J Sports Med 38: 129-133, 2004.
doi:10.1136/bjsm.2002.000760
PMid:15039245 PMCid:1724779
102. Piacentini M, Meeusen R, Buyse L, De Schutter G and De Meirleir K. No Effect of a Selective Serotonergic/Noradrenergic Reuptake Inhibitor on Endurance Performance. Eur J Sport Sci 2: 2002.
103. Pitsiladis Y, Strachan A, Davidson I and Maughan R. Hyperprolactinaemia during prolonged exercise in the heat: evidence for a centrally mediated component of fatigue in trained cyclists. Exp Physiol 87: 215-226, 2002.
doi:10.1113/eph8702342
PMid:11856966
104. Pugh L, Corbett J and Johnson R. Rectal temperatures, weight losses, and sweat rates in marathon running. J Appl Physiol 23: 347-352, 2002.
105. Rasmussen P, Dawson EA, Nybo L, Van Lieshout JJ, Secher NH and Gjedde A. Capillary-oxygenation-level-dependent near-infrared spectrometry in frontal lobe of humans. J Cereb Blood Flow Metab 27:1082-1093, 2007.
106. Rasmussen P, Stie H, Nielsen B and Nybo L. Enhanced cerebral CO2 reactivity during strenuous exercise in man. Eur J Appl Physiol 96: 299-304, 2006.
doi:10.1007/s00421-005-0079-3
PMid:16284788
107. Richardson RS, Noyszewski EA, Leigh JS and Wagner PD. Lactate efflux from exercising human skeletal muscle: role of intracellular PO2. J Appl Physiol 85: 627-634, 1998.
108. Robson-Ansley P, Barwood M, Canavan J, Hack S, Eglin C, Davey S, Hewitt J, Hull J and Ansley L. The effect of repeated endurance exercise on IL-6 and sIL-6R and their relationship with sensations of fatigue at rest. Cytokine 45: 111-116, 2009.
doi:10.1016/j.cyto.2008.11.006
PMid:19097916
109. Robson-Ansley PJ, Blannin A and Gleeson M. Elevated plasma interleukin-6 levels in trained male triathletes following an acute period of intense interval training. Eur J Appl Physiol 99: 353-360, 2007.
doi:10.1007/s00421-006-0354-y
PMid:17165057
110. Roelands B, Goekint M, Heyman E, Piacentini MF, Watson P, Hasegawa H, Buyse L, Pauwels F, De SG and Meeusen R. Acute norepinephrine reuptake inhibition decreases performance in normal and high ambient temperature. J Appl Physiol 105: 206-212, 2008.
doi:10.1152/japplphysiol.90509.2008
PMid:18499777
111. Roelands B, Hasegawa H, Watson P, Piacentini MF, Buyse L, De SG and Meeusen R. Performance and thermoregulatory effects of chronic bupropion administration in the heat. Eur J Appl Physiol 105: 493-498, 2009.
doi:10.1007/s00421-008-0929-x
PMid:19002702
112. Roelands B, Hasegawa H, Watson P, Piacentini MF, Buyse L, De SG and Meeusen RR. The effects of acute dopamine reuptake inhibition on performance. Med Sci Sports Exerc 40: 879-885, 2008.
doi:10.1249/MSS.0b013e3181659c4d
113. Roti MW, Casa DJ, Pumerantz AC, Watson G, Judelson DA, Dias JC, Ruffin K and Armstrong LE. Thermoregulatory responses to exercise in the heat: chronic caffeine intake has no effect. Aviat Space Environ Med 77: 124-129, 2006.
114. Rudelle S, Ferruzzi MG, Cristiani I, Moulin J, Mace K, Acheson KJ and Tappy L. Effect of a thermogenic beverage on 24-hour energy metabolism in humans. Obesity 15: 349-355, 2007.
doi:10.1038/oby.2007.529
PMid:17299107
115. Saltin B, Gagge AP, Bergh U and Stolwijk JAJ. Body temperatures and sweating during exhaustive exercise. J Appl Physiol 32: 635-643, 1972.
116. Sawka MN and Wenger CB. Physiological responses to acute exercise-heat stress. In: Human Performance Physiology and Environmental Medicine at Terrestrial Extremes, edited by Pandolf KB, Sawka MN and and Gonzalez RR. 1988.
117. Secher NH, Seifert T and van Lieshout J. Cerebral metabolism and fatigue. J Appl Physiol 104: 306-314, 2008.
doi:10.1152/japplphysiol.00853.2007
PMid:17962575
118. Struder H, Hollmann W, Platen P, Donike M, Gotzmann A and Weber K. Influence of paroxetine, branched-chain amino acids and tyrosine on neuroendocrine system responses and fatigue in humans. Horm Metab Res 30: 188-194, 1998.
doi:10.1055/s-2007-978864
PMid:9623632
119. Sutton KG, Garrett EM, Rutter AR, Bonnert TP, Jarolimek W and Seabrook GR. Functional characterisation of the S512Y mutant vanilloid human TRPV1 receptor. Br J Pharmacol 146: 702-711, 2005.
doi:10.1038/sj.bjp.0706356
PMid:16100528 PMCid:1751200
120. Tarnopolsky MA. Caffeine and endurance performance. Sports Med 18: 109-125, 1994.
doi:10.2165/00007256-199418020-00004
PMid:9132918
121. Tarnopolsky MA. Effect of caffeine on the neuromuscular system - potential as an ergogenic aid. Appl Physiol Nutr Metab 33: 1284-1289, 2008.
doi:10.1139/H08-121
122. Tella SR, Ladenheim B and Cadet JL. Differential regulation of dopamine transporter after chronic self-administration of bupropion and nomifensine. J Pharmacol Exp Ther 281: 508-513, 1997.
123. Thomas MM, Cheung SS, Elder GC and Sleivert GG. Voluntary muscle activation is impaired by core temperature rather than local muscle temperature. J Appl Physiol 100: 1361-1369, 2006.
doi:10.1152/japplphysiol.00945.2005
PMid:16339343
124. Todd G, Butler JE, Taylor JL and Gandevia SC. Hyperthermia: a failure of the motor cortex and the muscle. J Physiol 563: 621-631, 2005.
doi:10.1113/jphysiol.2004.077115
PMid:15613373
125. Tucker R, Marle T, Lambert EV and Noakes TD. The rate of heat storage mediates an anticipatory reduction in exercise intensity during cycling at a fixed rating of perceived exertion. J Physiol 574: 905-915, 2006.
doi:10.1113/jphysiol.2005.101733
PMid:16497719 PMCid:1817748
126. Tucker R, Rauch L, Harley YX and Noakes TD. Impaired exercise performance in the heat is associated with an anticipatory reduction in skeletal muscle recruitment. Pflugers Arch 448: 422-430, 2004.
doi:10.1007/s00424-004-1267-4
PMid:15138825
127. Walters TJ, Ryan KL, Tate LM and Mason PA. Exercise in the heat is limited by a critical internal temperature. J Appl Physiol 89: 799-806, 2000.
128. Watson P, Hasegawa H, Roelands B, Piacentini MF, Looverie R and Meeusen R. Acute dopamine/noradrenaline reuptake inhibition enhances human exercise performance in warm, but not temperate conditions. J Physiol 565: 873-883, 2005.
doi:10.1113/jphysiol.2004.079202
PMid:15831540 PMCid:1464564
129. Watson P, Shirreffs SM and Maughan RJ. The effect of acute branched-chain amino acid supplementation on prolonged exercise capacity in a warm environment. Eur J Appl Physiol 2004.
130. White MD and Cabanac M. Exercise hyperpnea and hyperthermia in humans. J Appl Physiol 81: 1249-1254, 1996.
131. Willis WT and Jackman MR. Mitochondrial function during heavy exercise. Med Sci Sports exerc: 26: 1347-1354, 1994.
doi:10.1249/00005768-199411000-00009
132. Wilson TE, Cui J, Zhang R and Crandall CG. Heat stress reduces cerebral blood velocity and markedly impairs orthostatic tolerance in humans. Am J Physiol Regul Integr Comp Physiol 291: R1443-R1448, 2006.
doi:10.1152/ajpregu.00712.2005
133. Wilson TE, Cui J, Zhang R, Witkowski S and Crandall CG. Skin cooling maintains cerebral blood flow velocity and orthostatic tolerance during tilting in heated humans. J Appl Physiol 93: 85-91, 2002.
134. Wyndham C, Rogers G, Benade A and Strydom N. Physiological effects of the amphetamines during exercise. S Afr Med J 45: 247-252, 1971.
Key Words: Brain, Dopamine, Hyperthermia, Neurotransmiters, Review
Send correspondence to: Lars Nybo, Section of Human Physiology, Department of Exercise and Sport Sciences, University of Copenhagen, Universitetsparken 13, DK-2100 Copenhagen O, Denmark, Tel: 4535321620, Fax: 4535321600, E-mail:lnnielsen@ifi.ku.dk