Sports med 2006; 36 (10): 881-909

Sports Med 2006; 36 (10): 881-909  2006 Adis Data Information BV. All rights reserved.
Central Fatigue
The Serotonin Hypothesis and Beyond
Romain Meeusen,1 Philip Watson,2 Hiroshi Hasegawa,1,3 Bart Roelands1 andMaria F. Piacentini1,4 1 Department Human Physiology and Sportsmedicine, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium 2 School of Sport and Exercise Sciences, Loughborough University, Leicestershire, UK3 Laboratory of Exercise Physiology, Faculty of Integrated Arts and Sciences, Hiroshima University, Higashihiroshima, Japan 4 Department of Human Movement and Sport Sciences, Istituto Universitario di Scienze Motorie, Rome, Italy 2.1 Nutritional Manipulation of Neurotransmission: Branched-Chain Amino Acid, Tryptophan 2.2 Pharmacological Manipulation of Neurotransmission: Selective Serotonin Reuptake 3. The Use of Prolactin and Other Hormones as Peripheral Indices of Brain Neurotransmitter Activity 8964. Is ‘What We See What We Get': is the Evidence for Central Fatigue that Straightforward? . . . . 8975. Are There Other Possible Factors Responsible for Central Fatigue? . . . . . . . . . . . . . . 8986. Hyperthermia and Central Fatigue: Is There a Link with Brain Neurotransmitters? . . . . . . . . 900 The original central fatigue hypothesis suggested that an exercise-induced increase in extracellular serotonin concentrations in several brain regions contrib-uted to the development of fatigue during prolonged exercise. Serotonin has beenlinked to fatigue because of its well known effects on sleep, lethargy anddrowsiness and loss of motivation. Several nutritional and pharmacologicalstudies have attempted to manipulate central serotonergic activity during exercise,but this work has yet to provide robust evidence for a significant role of serotoninin the fatigue process. However, it is important to note that brain function is notdetermined by a single neurotransmitter system and the interaction between brainserotonin and dopamine during prolonged exercise has also been explored ashaving a regulative role in the development of fatigue. This revised central fatiguehypothesis suggests that an increase in central ratio of serotonin to dopamine is Meeusen et al. associated with feelings of tiredness and lethargy, accelerating the onset offatigue, whereas a low ratio favours improved performance through the mainte-nance of motivation and arousal. Convincing evidence for a role of dopamine inthe development of fatigue comes from work investigating the physiologicalresponses to amphetamine use, but other strategies to manipulate central catecho-lamines have yet to influence exercise capacity during exercise in temperateconditions. Recent findings have, however, provided support for a significant roleof dopamine and noradrenaline (norepinephrine) in performance during exercisein the heat. As serotonergic and catecholaminergic projections innervate areas ofthe hypothalamus, the thermoregulatory centre, a change in the activity of theseneurons may be expected to contribute to the control of body temperature whilst atrest and during exercise. Fatigue during prolonged exercise clearly is influencedby a complex interaction between peripheral and central factors.
The limits of performance during prolonged ex- Many factors influence the capacity to perform ercise have been the subject of numerous physiolog- prolonged exercise and the relative importance of ical and psychological studies. Fatigue has tradition- these different factors varies depending on the dura- ally been attributed to the occurrence of a ‘metabolic tion of exercise, the intensity of the work, the mode endpoint', where muscle glycogen concentrations of exercise and the environmental conditions.
are depleted, plasma glucose concentrations are re- Therefore, when reconsidering the central fatigue duced and plasma free fatty acid levels are elevated.
hypothesis, it is important to reflect on all these However, the causes of fatigue are believed to be of elements. The purpose of this article is to review the both peripheral and central origin, therefore, fatigue possible cerebral responses during prolonged exer- should be acknowledged as a complex phenomenon cise and their possible connection to fatigue. We influenced by both peripheral and central factors.[1,2] will evaluate the scientific evidence for the originalcentral fatigue hypothesis by looking at the underly- The notion that the CNS is involved in the devel- ing neurobiological mechanism. This article will opment of fatigue is not new. Early work by Ales- highlight other possible central factors that may be sandro Mosso (1904) crudely demonstrated a re- important in the development of fatigue, in particu- duced capacity to perform repeated muscle contrac- lar when exercise is performed in a warm environ- tions following a mental effort, resulting in the ment. As body temperature appears to be an impor- development of the term ‘mental fatigue'.[3] Later, tant factor in the fatigue process under conditions of Romanowski and Grabiec[4] mentioned the possibil- heat stress, the underlying neurochemical mecha- ity of centrally mediated fatigue during exercise.
nisms implicated in the control of thermoregulation They linked serotonin to a possible inhibition of whilst at rest and during exercise will also be ex- brain oxidoreductive processes, while others[5,6] highlighted the role of dopamine in the developmentof fatigue. Since these original works, many ad- 1. Fatigue: the Central
vances have been made to clarify the role of the CNS in the development of fatigue. While therehave been a number of neurobiological mechanisms Fatigue during prolonged exercise has been de- proposed to explain the apparent loss of neural drive fined as the inability to maintain the required or referred to as central fatigue, the neurotransmitter expected power output that leads to a loss of per- hypothesis first put forward by Acworth et al.,[7] formance in a given task.[9] Several lines of evidence then later developed by Newsholme et al.,[8] has indicate that fatigue develops gradually and there is received the greatest academic recognition to date.
a reduction in the maximal force a muscle can  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) produce from the outset of prolonged exercise.
cursor for the synthesis of serotonin, and increased Therefore, it may be more useful to define fatigue as TRP availability to the serotonergic neurons results any exercise-induced reduction in the ability to exert in an increase in cerebral serotonin levels, because muscle force or power regardless of whether or not the enzyme that converts TRP to serotonin (trypto- the task can be sustained.[10] Since much of the work phan hydroxylase) is not saturated under normal in this area is interested in the development of physiological conditions. Consequently, the trans- fatigue during prolonged exercise, fatigue under port of TRP into the brain is considered to be the these conditions is often defined as a failure to rate-limiting step in the synthesis of serotonin, with continue working at a given exercise intensity.[11] an increase or decrease in brain TRP availabilityproducing a corresponding change in the rate of Factors thought to be important in the develop- serotonin synthesis within the CNS.[15] ment of peripheral fatigue during prolonged exer-cise include the depletion of muscle glycogen,[12] It was initially believed that the concentration of which is thought to limit the rate of adenosine plasma TRP was the only determinant of serotonin diphosphate rephosphorylation, and the progressive synthesis;[16] however, subsequent work has gradu- loss of body fluids resulting in increased cardiovas- ally revealed that the situation is complicated by cular, metabolic and thermoregulatory strain. The additional factors relating to the transport of TRP latter is particularly important when exercise is per- across the BBB. TRP binds to albumin in the blood, formed in warm ambient conditions, as it elevates a protein transporter shared with free-fatty acids body heat storage, accelerating the development of (FFA), and in the systemic circulation only a small hyperthermia.[13] Thus, peripheral fatigue encom- fraction (10–20%) is present as free TRP (f-TRP) at passes events that occur independently of the CNS, rest. There is limited evidence for a relationship including disturbances to neuromuscular transmis- between plasma f-TRP and brain TRP content under sion, sarcolemma excitability and excitation-con- resting conditions.[17,18] However, during exercise, traction coupling.
the concentration of plasma f-TRP, rather than total- The central fatigue hypothesis is based on the TRP, has been identified as a key factor in determin- assumption that during prolonged exercise the syn- ing the rate of cerebral TRP uptake during exercise, thesis and metabolism of central monoamines, in with a strong positive relationship reported betweenchanges in plasma f-TRP and brain TRP content.[19] particular serotonin, dopamine and noradrenaline(norepinephrine) are influenced. It was first suggest- The apparent difference in the size of the TRP pool ed by Newsholme et al.[8] that during prolonged available for transport into the CNS may result from exercise increased brain serotonergic activity may changes in cerebral blood flow. Cerebral blood flow augment lethargy and loss of drive, resulting in a is markedly increased to a large part of the brain reduction in motor unit recruitment. This, in turn, during exercise[20] and this increase in blood veloc- may influence the physical and mental efficiency of ity may limit the effectiveness of the large neutral the exercising individual, factors that could be re- amino acid carrier at removing TRP from albumin.
garded as central fatigue.
The mobilisation of FFA from adipose tissue by The serotonergic system has been suggested as adrenaline (epinephrine)-stimulated lipolysis has an important modulator of mood, emotion, sleep and been proposed to be important to the development of appetite, and thus has been implicated in the control serotonin-mediated fatigue during prolonged exer- of numerous behavioural and physiological func- cise.[8] Plasma FFA concentrations typically in- tions.[14] Serotonin is unable to cross the blood-brain crease progressively throughout prolonged low- to barrier (BBB), therefore, cerebral neurons are re- moderate-intensity exercise, particularly following a quired to synthesise it for themselves. The initial period of food deprivation (e.g. an overnight fast).
step in this process is the uptake of the amino acid Although there appears to be a near linear relation- tryptophan (TRP), across the BBB. TRP is the pre- ship between plasma FFA and the rate of FFA  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) Meeusen et al. utilisation,[21] this increase occurs as the mobilisa- f-TRP and BCAA share a common transporter tion of FFA from the adipose tissue often slightly across the BBB, a reduction in competing large- exceeds uptake by the working muscles.[22] When neutral amino acids would increase the uptake of muscle and liver glycogen stores are nearing deple- TRP into the CNS.
tion, FFA mobilisation can increase disproportion- It would be naive to believe that the only regula- ately over the rate of transport into the muscle, tor of serotonin release and synthesis is the delivery resulting in a marked elevation in plasma FFA con- of TRP to a serotonergic neuron. A number of subtle centrations.[23] As FFA molecules bind to albumin, control factors have been proposed to influence se- conformational changes occur that result in the lib- rotonin synthesis, including the availability of oxy- eration of TRP from its binding site,[24] consequent- gen and pteridine – cofactors that are required in the ly increasing the proportion of TRP circulating in a hydroxylation of TRP.[14] serotonin release is thought to be influenced by the activity of other The entry of TRP into the brain competes with neurotransmitter systems, including dopamine and the transport of branched-chain amino acids (BCAA GABA as well as cerebral glucose availability.[29] – leucine, isoleucine and valine) across the BBB, as Additionally, increases in extracellular serotonin they are mediated by the same carrier system.[25] concentrations have been demonstrated to activate This led to the suggestion that the plasma concentra- serotonin 5-HT1A (and potentially 5-HT1B/1D) tion ratio of TRP to competing amino acids is impor- autoreceptors producing a negative feedback, tant in determining the rate of cerebral TRP uptake, normalising serotonin levels due to a reduction in with an increase in this ratio leading to increased the firing rate of the neuron.[30] An overview of the brain TRP and serotonin content.[15] Because, pro- major serotonergic receptors studied in relation to longed exercise results in FFA release from adipose central fatigue is presented in table I.
tissue, plasma concentrations of both FFA and f- Furthermore, it is possible that the interaction TRP increase, producing a corresponding increase between brain serotonin and dopamine during pro- in cerebral serotonin levels. According to the hy- longed exercise could play a regulative role in the pothesis of Newsholme et al.,[8] this change in brain onset of fatigue.[31] Unknowingly, dopamine was neurochemistry results in subjective sensations of one of the first neurotransmitters to be linked to lethargy and tiredness, causing an altered sensation central fatigue, through the study of amphetamine of effort, perhaps a differing tolerance of pain/dis- use. Animal studies[5,32,33] showed that increased comfort and a loss of drive and motivation to contin- brain dopamine activity occurs during prolonged ue exercise.
physical activity and this may be important to exer- Based on the literature presented above, the un- cise performance.[31] The association between exer- derlying mechanism behind the central fatigue hy- cise performance and dopaminergic activity be- pothesis as proposed by Newsholme et al.[8] can be comes clear when we consider that dopamine plays divided into two interrelated sections: an important role in motivation, memory, reward 1. Under resting conditions, the majority of TRP and attention. Evidence suggests that animals are circulates in the blood loosely bound to albumin, a motivated to perform behaviours that stimulate transporter shared with f-FFA. The shift in substrate dopamine release in the ventral tegmental area[34] mobilisation occurring as exercise progresses causes and addiction is a common feature of a number of an increase in plasma FFA concentration. This dis- dopaminergic drugs. The dopamine activity in the places TRP from binding sites on albumin, leading caudate and accumbens nuclei appears to be in- to a marked increase in f-TRP. f-TRP is then readily volved in the control of voluntary movement and available for transport across the BBB.
locomotion.[35] Noradrenergic neurons seem to be 2. Plasma BCAA concentrations either fall[26,27] or involved in the regulation of attention, arousal and are unchanged[28] during prolonged exercise. Since sleep-awake cycles as well as learning and memory,  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) Table I. Location and physiological function of serotonin 5-HT receptor subtypes commonly manipulated in exercise physiology (reproduced
from Cooper et al.,[14] by permission of Oxford University Press, Inc.)
High-density regions Raphe nuclei, hippocampus Hyperpolarisation reduces serotonin secretory releasing frequency. The autoreceptorsregulate serotonin concentration in the synaptic cleft and consequently the extent ofstimulation of the postsynaptic 5-HT receptorsPostsynaptic 5-HT1A receptors are thought to be involved in thermoregulation,hypotension and sexual behaviour Substantia nigra, globus Do not close or open ion channels, instead coupled to the adenylyl cyclase signal transduction pathwayThrough interaction with serotonin transporter, 5-HT1B receptors modulate serotoninrelease. The autoreceptors function is similar to the 5-HT1A receptor Globus pallidus, substantia Do not close or open ion channels, instead coupled to the adenylyl cyclase signal nigra, basal ganglia transduction pathwayThrough interaction with serotonin transporter, 5-HT1B receptors modulate serotoninrelease. The autoreceptors function is similar to the 5-HT1A receptor Cortex, hippocampus, facial Opens or closes K+ channels, activates several protein kinases and signal transduction through phosphoinositide hydrolysis5-HT2 receptor sensitivity is physiologically higher than that of pre- or postsynaptic5-HT1 receptors5-HT2 receptors have been associated with mood regulation and hallucinogenic activity Widely distributed throughout Opens or closes K+ channels, activates several protein kinases and signal transduction through phosphoinositide hydrolysis5-HT2C receptors have been associated with mood regulation, energy balance andhallucinogenic activity5-HT2C receptors are involved in the control of the activity of the central dopaminergicsystem Peripheral neurons, entorhinal Supports 5-HT2 receptor activation by concomitant membrane depolarisationcortex, area postrema Suppression of 5-HT3 receptor activity may contribute to the action of antidepressants anxiety, pain, mood and brain metabolism.[36] In a sense of effort and its relationship with the willing- similar manner to the dopaminergic system, nora- ness to start and continue exercise can be signifi-cantly influenced by the CNS.[2,8,31,37,38] drenergic mechanisms are involved in feelings ofreward. Noradrenaline has also been implicated in 2. Central Fatigue and Serotonin:
aetiology of depression.
the Evidence
Based on these observations, Davis and Bailey[31] developed Newsholme's original hypothesis. Rather Much of the attraction of the hypothesis de- than the proposition that central fatigue was exclu- scribed by Newsholme et al.[8] was the potential for sively mediated through changes in the synthesis nutritional manipulation of neurotransmitter precur- and metabolism of serotonin, the findings of this sors to delay the onset of central fatigue and poten- series of studies led to the suggestion that both tially enhance performance. In recent years, a num- serotonin and dopamine were important to the fa- ber of studies have attempted to attenuate the in- tigue process. This revised central fatigue hypothe- crease in central serotonin levels through dietary sis suggests that an increase in the brain content ratio supplementation with specific nutrients, including of serotonin to dopamine is associated with feelings amino acids and carbohydrate (CHO). Other studies of tiredness and lethargy, accelerating the onset of have employed pharmacological manipulations to fatigue, whereas a low ratio favours improved per- alter the central extracellular neurotransmitter con- formance through the maintenance of motivation centrations. Table II and table III give an overview and arousal. Given the strong relationship between of the human and animal studies that have attempted alterations in neurotransmitters and neuromodu- to manipulate brain neurotransmission through nu- lators and an individual's mood, it is likely that the tritional supplementation with amino acids or CHO  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) 2006 Adis Data Information BV. All rights reserved.
Table II. Effect of nutritional and pharmacological manipulation of central neurotransmission on exercise in humans
Segura and Ventura[39] ↔ RPE, HR, ˙VO2 Blomstrand et al.[40] 30km cross-country or 42.2km ↑ Exercise perf in slower runners ↔ Exercise perf in faster runners Stensrud et al.[41] Wilson and Maughan[42] Paroxetine (SSRI) ↔ RPE, HR, ˙VO2, Tcore VO2max up to 255 min ↓ f-TRP : BCAA
Fluoxetine (SSRI) Hassmen et al.[45] 30km cross-country ↔ Exercise perf ↑ Cognitive perf Varnier et al.[46] Pannier et al.[47] Pizotifen (5-HT2C antagonist) Blomstrand et al.[48] BCAA or BCAA + CHO ↔ Tex, HR, RPE, ˙VO2, Tcore van Hall et al.[27] Texh 70–75% Wmax Madsen et al.[50] 100km TT (cycling) ↔ TT perf, BCAA Marvin et al.[51] Buspirone (5-HT1A agonist) Meeusen et al.[52] L-DOPA (D precursor) Ritanserin (5-HT2A/2C antagonist) Blomstrand et al.[53] 60 min 70% Wmax, 20 min 100% Wmax Mittleman et al.[54] ↔ Tcore, mental perf CHO or CHO + BCAA Intermittent shuttle running to fatigue ↑ Tex, CHO/CHO + BCAA vs placebo ↔ Tex, CHO vs CHO + BCAA Struder et al.[56] BCAA, TYR, paroxetine (SSRI) ↔ Tex with BCAA, TYR Sports Med 2006; 36 (10) Meeusen et al.[57] Fluoxetine (SSRI) Cycle TT ( 90 min) ↔ TT perf, RPE, PRL Parise et al.[58] Acute fluoxetine (SSRI) Wingate and 80% ˙ VO2max to fatigue Meeusen et al. Chronic fluoxetine (SSRI) Wingate and 90% ˙ VO2max to fatigue Continued next page 2006 Adis Data Information BV. All rights reserved.
Table II. Contd
Piacentini et al.[59] Venlafaxine (serotonin/NA agonist) Cycle TT ( 90 min) ↔ TT perf, RPE, HR Piacentini et al.[60] Reboxetine (NA agonist) Cycle TT ( 90 min) ↔ TT perf, RPE, HR ↑ PRL, β-END, NA, ACTH Sgherza et al.[61] Naloxolone (opioid antagonist) Piacentini et al.[62] Bupropion (D/NA agonist) Cycle TT ( 90 min) ↔ TT perf, RPE, HR ↑ PRL, ACTH, NA Bridge et al.[63] Buspirone (5-HT1A agonist + D2 Positive relationship between TTE and antagonist) or Buspirone + pindolol non-serotonin component (5-HT1A antagonist) ↑ voluntary activation 2 min maximum contraction Jacobs and Bell[65] Modafinil (α1 adrenergic agonist) Strachan et al.[66] Paroxetine (SSRI) ↔ Tex, PRL, cortisol Cheuvront et al.[67] VO2max + 30 min TT at ↔ TT perf, HR, Tcore, mental perf Watson et al.[68] ↔ Tex, Tcore, HR, RPE Strachan et al.[69] Pizotifen (5-HT2C antagonist) 40km TT at 35.5°C Winnick et al.[70] Intermittent shuttle running to fatigue ↑ Tex, cognitive perf Watson et al.[71] Bupropion (D/NA agonist) 60 min 55% Wmax + TT at 18 and 30°C I: ↔ TT perfII: ↑ TT perf, Tcore, HR ↔ RPE, thermal comfort Sports Med 2006; 36 (10) Blomstrand et al.[72] 180 min 200 ± 7W ↓ net cerebral TRP uptake ACTH = adrenocorticotropin hormone; β-END = β-endorphin; BCAA = branched-chain amino acids; CAF = caffein; CHO = carbohydrates; D = dopamine; F = females; f-TRP = free
tryptophan; HR = heart rate; L-DOPA = L-dihydroxyphenylalanine; L-TRP = L-tryptophan; M = males; NA = noradrenaline; NH3 = ammonia; perf = performance; PRL = prolactin;
RPE = ratings of perceived exertion; SSRI = selective serotonin reuptake inhibitor; Tcore = core temperature; Tex = exercise time; Texh = time to exhaustion; TRP = tryptophan; TT =
time trial; TTE = run time to exhaustion; TYR = tyrosine; ˙
VO2 = oxygen uptake; ˙
VO2max = maximal oxygen uptake; ˙
VO2peak = peak oxygen uptake; Wmax = maximal wattage; ↓
indicates decrease; ↑ indicates increase; ↔ indicates no effect.
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Table III. Effect of nutritional and pharmacological manipulation of central neurotransmission on exercise in animals
Jacobs and Eubanks[73] 64 S-D rats + controls Tilt-cage and 3h activity ↓ Activity in dose-dependent manner 5-HTTP inj. IP-SC 10 S-D rats/group Amphetamine (D agonist) ↑ Tex in dose-dependent manner Chlorpromazine inj. I-V (tranquilliser) Texh (9.14 m/min) at 35°C Chlorpromazine and L-TRP: ↑ Tex and produced hypothermia Apomorphine (D agonist) Apomorphine: ↑ Tex Clonidine (α2-adrenergic agonist) Clonidine: ↔ Tex Chaouloff et al.[5] 5 Wistar rats/group Amphetamine (D agonist) 60 min treadmill ex (20 m/min, Amphetamine: ↓ brain serotonin Pargyline (MAO-B inhibitor) Pargyline: ↑ brain DOPAC Alpha-methyl-p-tyrosine: ↑ brain Haloperidol (D antagonist) Haloperidol: no effect Chaouloff et al.[75] 6–7 Wistar rats/group NSD 1015 (serotonin 5-HT receptor 90 min ex (20 m/min) NSD 1015: serotonin synthesis impaired in hippocampus Hillegaart et al.[76] 8-OHDPAT (5-HT1A agonist) inj. SC Open field activity and treadmill Wilckens et al.[77] TFMPP (5-HT antagonist) Spontaneous running wheel mCPP: ↓ activity 5-HT1C mCPP (5-HT1C agonist) Effect abolished by antagonist DOI (5-HT2 agonist)QD (5-HT agonist) Bailey et al.[78] mCPP (5-HT1C agonist) Texh (20 m/min, 5% grade) ↓ Tex in dose-dependent manner Bailey et al.[32] QD (5-HT agonist) Texh (20 m/min, 5% grade) QD: ↓ Tex in dose-dependent manner LY 53857 (5-HT receptor antagonist) LY: ↑ Tex at highest dose (1.5 mg/kg) Bailey et al.[79] 8 Wistar rats/group Texh (20 m/min, 5% grade) QD (1 mg/kg): ↓ Tex by 32% LY (1.5 mg/kg): ↑ Tex by 26% Verger et al.[80] Texh (16 m/min, 5% grade) BCAA: ↔ TexCHO: ↑ Tex Meeusen et al.[81] 60 min ex (12 m/min) ↑ serotonin in hippocampusNo effect on fatigue Calders et al.[82] Texh (20 m/min 8% grade) ↑ Tex, blood NH3 Farris et al.[83] L-TRP or L-TRP/CHO ↓ Tex with L-TRP and L-TRP/CHO Calders et al.[84] Texh (20 m/min 8% grade) ↑ Tex with BCAA, CHO, CHO + BCAA ↔ Tex with saline Sports Med 2006; 36 (10) CHO + BCAA inj. IP Connor et al.[85] Reboxetine (NA agonist) Dose-dependent attenuation of theswim test induced increases in Meeusen et al. serotonin + D activity Continued next page or by the administration of pharmacological agents that are known to act directly on the CNS.
2.1 Nutritional Manipulation of = 5-HT antagonist; Neurotransmission: Branched-Chain AminoAcid, Tryptophan and = intraperitoneal;
IP
↓ indicates decrease; = Sprague-Dawley; As TRP competes with BCAA for transport , striatal D, DOPAC = branched chain amino acids; serotonin with L-valine across the BBB into the CNS,[15] reducing the plas- ↑ hippocampus serotonin with ex ↔ Positive relationship between running distance and BCAA-based solution ↔ ↓ HR, heat storage ↓ heat loss ↑ heat production, T ↔ . = injection;
inj
ma concentration ratio of f-TRP to BCAA through the ingestion of exogenous BCAA has been suggest- = noradrenaline; ed as a practice to attenuate the development of central fatigue. The first investigation undertaken to = subcutaneous; test the efficacy of BCAA supplementation at atten- = maximal oxygen uptake; uating serotonin-mediated fatigue was a field study of the physical and mental performance of male volunteers competing in either a marathon or a (20 m/min 5% grade) (18 m/min 5% grade) 30km cross-country race.[40] The findings suggested 60 min ex (25 m/min) Activity wheel + treadmill running (60 min at 5 and 25 m/ 120 min ex (10 m/min) that both physical (race time) and mental (colourand word tests) performance were enhanced in those receiving BCAA prior to exercise. However, en- hanced exercise performance was only witnessed insubjects completing the marathon in times slower = 6-hydroxydopamine; than 3 hours 5 minutes. The authors suggested thefaster runners may have developed an increased = monoamineoxidase-B; = quipazine dimaleate: 5-HT agonist; resistance to the feelings associated with central and peripheral fatigue as a result of their training. It is = 5-HT antagonist; = 3,4-dihydroxyphenylacetic acid; worth noting that this was a field-based study, and assuch has a degree of ecological validity, but the findings may be limited due to a lack of experimen- L-valine inj. I-V Methamphetamine (D uptake inhibitor) BCAA + glutamine + arginine inhibitor) inj. I-V Tetrodotoxin (sodium channel blocker) perfusion into the PO/AH tal control.
While there is some additional evidence of = 5-hydroxytryptophan; = 5-HT antagonist; BCAA ingestion influencing ratings of perceivedexertion (RPE)[53] and mental performance,[45,92] the = time to exhaustion; results of several apparently well controlled labora- tory studies have not demonstrated a positive effecton exercise capacity or performance. No ergogenic benefit has been reported during prolonged fixed = L-tryptophan; intensity exercise to exhaustion,[27,48,53,56] prolonged time trial performance,[45,50] incremental exercise[46] = exercise time; or intermittent shuttle-running.[55] Given the clear indicates no effect.
association between cognitive function/performance = preoptic area and anterior hypothalamus; and brain neurotransmission, it seems unusual that = 5-hydroxytryptamine (serotonin); few studies have attempted to evaluate the effects of Table III.
Gomez-Merino et al.
Kalinski et al.
Smriga et al.
Rodrigues et al.
Soares et al.
Hasegawa et al.
= carbohydrates; intraventricular; exercise and central fatigue on mental performance.
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Sports Med 2006; 36 (10) Meeusen et al. Work conducted by Mittleman et al.[54] has pro- performed under temperate conditions, the response vided some support for BCAA and the apparent role appears to be different in animals, where a clear of serotonin in the fatigue process. A 14% increase increase in exercise capacity[82,84] and free running in capacity to perform low intensity (40% maximal activity[88] has been shown. A study conducted by oxygen uptake [ ˙ VO2max]) exercise was reported fol- Verger et al.[80] observed no difference in time to lowing BCAA supplementation when compared exhaustion following BCAA ingestion in rats when with a polydextrose placebo. No difference in pe- compared with a placebo condition, but it is not ripheral markers of fatigue was reported between the clear why these results fail to agree with those of two exercise bouts. The authors concluded that the Calders et al.[82,84] The development of in vivo brain supplementation regimen was successful in limiting microdialysis has enabled the direct analyses of the entry of TRP into the CNS, attenuating seroto- extracellular neurotransmitters and metabolites from nin-mediated fatigue. However, the unique aspect of the brain of resting and active animals with limited this study was that the trials were undertaken in a tissue trauma. Meeusen et al.[81] demonstrated that warm environment (34.4°C), with subjects seated at increased TRP availability resulted in an elevation rest for 2 hours before exercise in these conditions.
in extracellular serotonin and 5-hydroxyindoleacetic BCAA supplementation began 60 minutes prior the acid (5-HIAA) concentrations in 24-hour fasted rats.
start of exercise, resulting in a 2- to 3-fold reduction When TRP was administered prior to 60 minutes of in the plasma concentration ratio of f-TRP to treadmill running, the exercise serotonin response BCAA. In contrast, two subsequent studies have was amplified. Surprisingly, although the extracel- failed to support an effect of BCAA supplementa- lular serotonin concentration increased by >100%, tion on exercise capacity in the heat.[67,68] The role of there were no signs of early fatigue, with all animals the CNS in the development of fatigue during pro- able to finish the total running session. Evidence for longed exercise in a warm environment is discussed the role of BCAA in limiting TRP entry into the in section 6.
CNS and attenuating the increase in serotonin hasbeen reported in rodents using in vivo brain microdi- These conflicting findings question whether the alysis.[86] During the placebo trial (saline infusion), a attenuation of TRP uptake through the provision ofexogenous BCAA can significantly influence cen- progressive increase in extracellular serotonin was tral neurotransmission, but such effects may be in- apparent in the hippocampus as exercise continued, fluenced by the exercise and supplementation proto- but this elevation was abolished when exercise was col employed as well as the group of subjects stud- preceded by a peripheral infusion of valine.
ied. These methodological differences make While there are reports of TRP supplementation comparisons between studies difficult. In particular, producing a marked reduction in the exercise capac- incremental or high-intensity protocols may not be ity of horses[83] and rodents,[90] Segura and Ventu- ideal tests, due to the relatively short duration of ra[39] reported a 49% increase in time to exhaustion exercise and co-ingestion with CHO may mask any following L-TRP supplementation. The authors of potential ergogenic benefit (see section 5). Addi- this study hypothesised that administration of L- tionally, a time delay is thought to exist between TRP before exercise could contribute to a decreased changes in peripheral amino acid availability and the sense of discomfort and pain associated with pro- cerebral uptake of f-TRP,[93] meaning that the pre- longed exercise, but these data are confounded by exercise ingestion period employed in some investi- the spectacular improvement of two of the eight gations may have been insufficient to alter brain subjects (160% and 260% increase in running time).
neurotransmission significantly during the protocol Subsequent work investigating the ingestion of be- tween 1.2 and 3.0g of TRP immediately prior to the While support for a benefit of BCAA ingestion in start of exercise produced no effect on exercise humans is limited, particularly when exercise is capacity in human subjects.[27,41,49] In particular,  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) Stensrud et al.[41] failed to demonstrate a change in TRP to BCAA in a dose-dependent manner. Exer- exercise capacity following 24 hours of tryptophan cise capacity during CHO trials was increased over supplementation. The findings of this study appear the placebo, suggesting CHO ingestion as an effec- particularly convincing due to the unusually large tive means of delaying the onset of central fatigue, sample size studied (49 subjects), although the in- but it is difficult to interpret the contribution of tensity of exercise was high (100% ˙ central factors from the widely reported benefits of this may have limited the efficacy of the treatment.
CHO at attenuating peripheral fatigue. Recent work Although the ratio between TRP and BCAA may has demonstrated that CHO ingestion during exer- be changed by oral supplementation of BCAA or cise attenuated the cerebral uptake of TRP as well as TRP, the net effect on the brain is not yet clear. This preventing the development of hypoglycaemia, sup- was demonstrated by Nybo et al.[94] who evaluated porting these initial findings.[72] The importance of the cerebral balances of dopamine, tyrosine and CHO availability to the CNS is discussed in detail in TRP, as well as the cerebral oxygen-to-CHO uptake ratio during prolonged exercise with a normal orelevated core temperature. They reported a positive 2.2 Pharmacological Manipulation of relationship between cerebral TRP balance and the Neurotransmission: Selective Serotonin arterial TRP concentration and this was a better Reuptake Inhibitors predictor of TRP uptake than the plasma concentra-tion ratio of f-TRP to BCAA. However, there was Manipulation of central neurotransmission only a net uptake of TRP by the brain in half the through the administration of pharmacological subjects tested, and this response was not influenced agents dates back to the 19th century, where opium by body temperature. Failure to observe any in- and bromides were commonly used. The introduc- crease in cerebral TRP uptake when hyperthermia tion of antipsychotics for the treatment of schizo- does not support a significant role of serotonin in the phrenia and significantly, fluoxetine (Prozac),1
development of central fatigue in the heat. The started the widespread trend for the prescription of importance of central fatigue during prolonged exer- drugs acting on the CNS for the treatment of depres- cise in a warm environment is discussed in section 6.
sion. Today these drugs are used in the treatment of It appears that there is limited or only circumstan- a number of psychiatric disorders (including anxiety tial evidence to suggest that exercise performance in disorders, obsessive compulsive disorder); conse- temperate conditions can be altered by nutritional quently, the pharmaceutical industry is constantly manipulation through TRP or BCAA supplementa- producing novel, more selective agents. The world- tion. Another nutritional strategy that may influence wide prescribing rates for drugs of this nature have serotonin synthesis, and potentially the development increased dramatically over the last decade. There of central fatigue, is CHO feeding. The ingestion of has been a >2-fold increase in prescription rates for CHO suppresses lipolysis, lowering the circulating antidepressants alone reported in Australia, the UK concentration of plasma FFA and consequently lim- and the US. This may be due to an increase in the iting the exercise-induced rise in f-TRP. Recognis- spectrum of treatments available, improved recogni- ing this, Davis et al.[43] suggested CHO ingestion as tion of mental ill health, and the pressure to pre- a means of reducing cerebral TRP uptake. A 5- to 7- scribe drugs in favour of other treatments.
fold increase in the plasma concentration ratio of f- A series of studies by Bailey et al.[32,78] examined TRP to BCAA was reported under placebo condi- the effects of pharmacological manipulation of brain tions. Supplementation with a 6% or 12% CHO serotonin levels in rats through the administration of solution attenuated the increase in plasma FFA and specific 5-HT receptor agonists and antagonists.
f-TRP, reducing the plasma concentration ratio of f- This original work provided convincing evidence The use of trade names is for product identification purposes only and does not imply endorsement.
 2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) Meeusen et al. for a role of serotonin in the development of fatigue, other SSRI studies. The neuromuscular and per- with a dose-dependent reduction in exercise capaci- formance effects of short- and long-term exposure to ty reported when central serotonin activity was aug- fluoxetine have also been examined.[58] Serotonin mented by the acute administration of a general 5- has been demonstrated to alter an individuals' sensa- HT receptor agonist.[78] Brain serotonin and tion of pain, and this study differs from many others dopamine content progressively increased during in this area by investigating whether manipulation of exercise, but at the point of exhaustion a marked fall serotonergic neurotransmission could alter the re- in tissue dopamine content was apparent. Further- sponse to high-intensity and resistance exercise.
more, exercise capacity was enhanced by a 5-HT However, short- and long-term SSRI intake failed to receptor antagonist (LY-53857), although this was influence force production during maximal volunta-ry contractions or high-intensity exercise perform- apparent only when the highest dose was adminis- tered.[32] These alterations to exercise capacity oc- Several possible factors such as exercise proto- curred without any change in core temperature, cir- col, different dosages or drug utilisation might help culating metabolites or stress hormones.[79] Addi- explain the conflicting results observed. While there tionally, muscle glycogen concentrations at fatigue is some evidence that short-term SSRI ingestion can were higher when a 5-HT receptor agonist reduce an individual's capacity to perform pro- (quipazine dimaleate) was administered, suggesting longed exercise,[42,44,56] it has been suggested that that the accelerated fatigue did not occur as a result this occurred due to a disturbance in regulatory of limited glycogen availability. It is important to homeostasis of the serotonin system, perhaps via a note that the highest doses of drugs given in these disruption in pre- or postsynaptic receptor func- studies were many times greater than would normal- tion[95] rather than an increase in the activity of the ly be administered for therapeutic cases.
serotonergic neurons. It was recently demonstrated The first human studies designed to investigate with functional magnetic resonance imaging that the effects of pharmacological manipulation of cen- several SSRIs, including paroxetine, can produce a tral serotonin on exercise capacity employed a class dose-dependent activation of the entire motor path- of drugs known as selective serotonin reuptake in- way in a way that favours motor output.[96] This hibitors (SSRIs). SSRIs are agents that selectively suggests that serotonin plays an important role in the inhibit the reuptake of serotonin into the presynaptic initiation of movement and the continuation of mo- nerve terminal, thus prolonging its action. They tor behaviour.
increase the concentration of serotonin present at thepostsynaptic receptors and have been widely admin- 2.3 Serotonin 5-HT Receptor Agonists istered in the treatment of various psychiatric disor- ders, in particular depression. Three studies haveinvestigated the effects of an acute dose of paroxe- Serotonin produces its effects through a variety tine (Paxil, Seroxat): two reporting a decrease of membrane-bound receptors. Serotonin and its in time to exhaustion,[42,56] while a recent study did receptors are found both in the central and peripher- not detect any difference in exercise capacity when al nervous system, as well as in a number of non- cycling at 60% ˙ VO2max in 32°C.[66] Fluoxetine neuronal tissues in the gut, cardiovascular system (Prozac) produced a reduction in exercise capaci- and blood. 5-HT receptors are diverse and numerous ty in subjects cycling at 70% ˙ VO2max to exhaus- and represent one of the most complex families of tion.[44] Meeusen et al.[57] demonstrated that per- neurotransmitter receptors. Over the past decade, formance of a 90-minute time trial at 65% maximal >14 different 5-HT receptors have been cloned wattage (Wmax) was not affected by fluoxetine, al- through molecular biological techniques. These though some of the hormonal and metabolic re- studies have helped to identify new therapeutic sponses to the drug observed were comparable with targets, and aided an understanding of the multiple  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) roles played by serotonin in the brain. Overall, seven 2.4 Combined Reuptake Inhibitors distinct families of 5-HT receptors (5-HT1-7) have Because of the complexity of brain functioning been identified, with as many as five within a given and the contradictory results from the studies that family. Only one of the 5-HT receptors is a ligand- tried to manipulate only serotonergic activity, it gated ion channel; the other six belong to the G appears unlikely that a single neurotransmitter sys- protein-coupled receptor family. In line with the tem is responsible for the central component of studies that used SSRIs to manipulate central ser- fatigue. In fact, alterations in serotonin, catecho- otonergic activity, there have been several studies lamines, amino acid neurotransmitters (glutamate, that used selective 5-HT agonists and/or antagonists GABA) and acetylcholine have all been implicated during prolonged exercise to fatigue. According to as possible mediators of central fatigue during exer- the central fatigue hypothesis, 5-HT agonists would cise.[37] These neurotransmitters are known to play a be expected to reduce exercise time to exhaustion, role in arousal, mood, motivation, vigilance, anxietyand reward mechanisms, and could therefore, if while 5-HT antagonists would imply an increase in adversely affected, impair performance. It is there- exercise capacity.
fore necessary to explore the different transmitter Pannier et al.[47] investigated the effect of the systems and their effect on the neuroendocrine re- 5-HT receptor antagonist pizotifen on endurance sponse to endurance exercise. Since these drugs are performance during treadmill exercise in humans.
used in the treatment of a wide variety of psychiatric Pizotifen administration did not alter exercise time disorders, the pharmaceutical industry is constantly to exhaustion in this study, with similar findings producing novel, with potential to act on one or reported in a recent investigation when performance more neurotransmitter, systems.
was measured on a 40km time trial in 35°C.[69] In a series of studies, we supplemented athletes with venlafaxine a combined serotonin/ Additionally, a specific centrally acting 5-HT2A/2C noradrenaline reuptake inhibitor,[59] reboxetine a no- antagonist did not influence performance on a bicy- radrenaline reuptake inhibitor[60] and bupropion, a cle trial to exhaustion at 65% Wmax.[52] Taken to- combined noradrenaline/dopamine reuptake inhibi- gether, these studies indicate that although one tor.[62] Athletes performed two exercise trials requir- would expect 5-HT antagonism to positively influ- ing the completion of a preset amount of work as ence performance, no difference was found neither quickly as possible ( 90 minutes), in a double-blind on time trial performance or exercise time to ex- randomised crossover design. None of the above- haustion. Marvin et al.[51] exercised subjects at 80% mentioned reuptake inhibitors influenced (either VO2max following oral administration of either pla- negatively or positively) exercise performance (fig- cebo or the partial 5-HT1A agonist buspirone. Rat- ure 1). Each drug clearly altered central neurotrans- ings of perceived exertion were higher following mission since different neuroendocrine effects wereobserved depending on the type of reuptake inhibi- buspirone and time to volitional fatigue fell signifi- tor administered, as illustrated in figure 2 for prolac- cantly by approximately one-third following bus- tin (PRL) and growth hormone. While serotonin is pirone. This study supports the possible central thought to induce PRL release, SSRI administration modulation of exercise tolerance by serotonergic did not increase the PRL response to exercise. Addi- pathways, although a role for dopamine cannot be tionally, the noradrenaline/dopamine reuptake in- excluded. While this drug is thought to primarily act hibitor was not able to decrease PRL release. More- as a 5-HT1A receptor agonist, it also produces a over, it appears that noradrenaline has a significant limited dopaminergic D2 antagonism,[63] which may enhancing effect on growth hormone concentra- have played a significant role in mediating this tions. This brings us back to the possible interaction between neurotransmitters and their mutual influ-  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) Meeusen et al. performance benefit following the administration of amphetamine to both rodents[33] and humans.[99,100] The ergogenic action of amphetamine is thought tobe mediated through the maintenance of dopamine release late in exercise. These findings have led to the widespread use of amphetamines in many endur- ance events, with a long history of abuse in cycling events in particular.
Animal studies show that at the point of fatigue dopamine extracellular concentrations are low, pos- Venlaf5-HT/NA Rebo sibly due to the interaction with brain serotonin,[78] Fig. 1. Effects of different reuptake inhibitors on 90-minute time trial
or a depletion of central catecholamines.[31] The performance at an ambient temperature of 18°C.[57,59,60,62,97,98] 5-HT
various studies that examined the influence of exer- = serotonin; D = dopamine; NA = noradrenaline.
cise on brain neurotransmitters indicate that bothcentral dopaminergic and serotonergic activity are ence on the hormonal response to a prolonged exer- influenced by exercise. Chaouloff et al.[5] examined cise protocol. Peripheral hormone concentrations if compounds known to affect dopamine activity in have been employed as markers of central neuro- the brain could modify the serotonin response in the transmitter activity and the application of these pe- brain during exercise. The dopamine metabolism ripheral indices of neurotransmission is discussed in was increased in serotonin-rich regions. Administra- tion of amphetamine, while increasing levels of TRPin the brain, diminished the formation of 5-HIAA, 2.5 Catecholaminergic Drugs suggesting that serotonergic activity was reduced.
The relative inhibition of synthesis of serotonin in- Dopamine and noradrenaline are neurotransmit- duced by running was thus potentiated by adminis- ters linked to the ‘central' component of fatigue for tration of amphetamine while α-methyl-p-tyrosine their well known role on motivation and motor (inhibitor of catecholamine synthesis) prevented this behaviour,[37,75] and are therefore thought to have an effect of exercise, and haloperidol (dopamine antag- enhancing effect on performance. Early pharmaco- onist) did not produce any significant change. Fur- logical manipulation of central neurotransmission to ther evidence for a role of dopamine in the develop- improve exercise performance focused largely on ment of central fatigue is provided by work conduct- the effects of amphetamines, with studies of this ed by Heyes et al.[6] Infusion of apomorphine (a nature undertaken by German scientists during the dopamine agonist) has been shown to prolong and Second World War. Amphetamine is a close ana- partially restore exercise capacity following destruc- logue of dopamine and noradrenaline, thought to act tion of dopaminergic neurons with 6-hydroxy- directly on catecholaminergic neurones to produce a dopamine. Additionally, pre-exercise treatment with marked elevation in extracellular dopamine concen- methamphetamine, which produces a depletion of trations. This response is believed to be mediated striatal dopamine, resulted in a marked reduction in through the stimulation of dopamine release from running time to exhaustion in rodents.[87] storage vesicles, inhibition of dopamine reuptakeand the inhibition of dopamine metabolism by Intracranial self-stimulation (ICSS) has been em- monoamineoxidase.[14] Amphetamines may also ployed as a model to induce exercise in rodents, limit the synthesis of serotonin through a reduction removing the need to administer aversive electric in TRP hydroxylase activity and a direct interaction shocks.[34] ICSS involves the implantation of an between dopamine release and serotonergic neuro- electrode into the ventral tegmental area, the origin transmission.[5] Studies have demonstrated a clear of the dopaminergic projection, which triggers elec-  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) trical stimulation to this area of the brain when the noradrenaline manipulation on exercise capacity in animal maintained a pre-determined running speed.
humans. The administration of L-3,4-dihydrox- The dopaminergic reward associated with ICSS has yphenylalanine (L-DOPA), an intermediate in the been reported to enable rats to run around 50% catecholamine pathway, has been employed to ef- longer when compared with the use of electric fectively bypass the rate-limiting step in dopamine shock,[34] while producing no effect on peripheral and noradrenaline synthesis. L-DOPA has been used variables relating to cardiovascular, metabolic or in the management of Parkinson's disease, a disor- thermoregulatory function.[101] Although studies in- der characterised by a loss of motor control and vestigating changes in central dopamine using elec- coordination, to maintain central dopamine neuro- tric shock grids to stimulate running should be transmission. Meeusen et al.[52] examined the effect viewed with caution as the stress associated with of L-DOPA on exercise capacity in endurance- this form of motivation has been demonstrated to trained males. Ingestion of L-DOPA 24 hours and significantly increase dopamine release,[102] it needs immediately before commencing exercise had no to be pointed out that these studies clearly demon- effect on submaximal time to exhaustion or periph- strate the involvement of the dopaminergic system eral cardiovascular or metabolic measures during in increasing performance.
Despite the apparent link between exercise and The recent development of brain imaging tech- catecholaminergic neurotransmission demonstrated nologies will help shed light on the effect of exercise in animals, there has been relatively little work on central neurotransmission, but the application of conducted to assess the effects of dopamine and these techniques are still in their infancy. Wang et Venlafaxine 5-HT/NA Fig. 2. Effects of a 90-minute time trial performance at an ambient temperature of 18°C on (a) the prolactin (PRL) concentration (mean ±
SD) and (b) the growth hormone (GH) concentration (mean ± SD).[57,59,60,62,98] 5-HT = serotonin; D = dopamine; NA = noradrenaline; rec =
recovery; # indicates significantly (p < 0.05) different from reboxetine; * indicates significantly (p < 0.05) different from bupropion.
 2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) Meeusen et al. al.[103] evaluated the effects of exercise on striatal dopamine and noradrenaline neurons innervating dopamine release in the human brain using positron the hypothalamus stimulates the synthesis of releas- emission tomography (PET) scans. They did not ing and inhibiting hormones that act directly on find significant changes in synaptic dopamine con- areas of the pituitary to trigger the release of hor- centration during vigorous treadmill exercise for 30 mones into the peripheral circulation. Adrenocorti- minutes. They concluded that this level of exercise cotropic hormone (ACTH) release from the pituitary does not induce changes in striatal dopamine release also exhibits control over the adrenal gland, influ- that are large enough to be detected with the PET encing cortisol release. This has led to the term the raclopride method. Thus it seems that experimental hypothalamic-pituitary-adrenal (HPA) axis.
evidence for a relationship between fatigue and While the hypothalamus receives input from a dopamine deficiency in the healthy human brain number of cerebral structures, it is clear that the during prolonged exercise is lacking at present.
stimulation of different receptors within the While there is good indirect evidence that catecho- neuroendocrine control sites produces a differing laminergic neurotransmission plays an important action on hormone release.[104,105] The application of role in the fatigue process, further evaluation of neuroendocrine tests to disturb central neurotrans- dopaminergic activity during exhaustive exercise is mission has provided insight into the relative contri- required before firm conclusions on the relevance of butions of serotonin, dopamine and noradrenaline in dopamine for central fatigue can be drawn.
the regulation of pituitary hormone release. Howev-er there remains a degree of uncertainty regarding 3. The Use of Prolactin and Other
the coordination of the endocrine response particu- Hormones as Peripheral Indices of Brain
larly under conditions of stress, including exer- There is a considerable body of evidence to indi- Although recent imaging techniques such as PET cate a role for several neurotransmitters in the regu- and single photon emission computed tomography lation of PRL, ACTH, cortisol and growth hormone scans are promising, it is difficult to directly deter- secretion.[104-106] The most important PRL inhibiting mine changes in central neurotransmission in human factor is dopamine, which acts on the two most subjects. While these methods are increasingly be- potent PRL-releasing factors: thyrotropin-releasing ing employed in a clinical setting, their use is re- hormone and oxytocin. While basal secretion of stricted in exercise physiology due to expense, ac- PRL is primarily regulated by tonic inhibition by cess to experienced operators and logistical dopamine, serotonergic regulation originates from problems associated with performing exercise in or cells in the dorsal raphe nucleus with activation of 5- close to the equipment. Therefore, the measurement HT1A, 5-HT2A/C, 5-HT3 receptors stimulating the of changes in circulating concentrations of peripher- secretion of PRL.[105] The neurons producing PRL al hormones has been employed as an index of inhibiting and releasing factors receive serotonergic innervation ascending mainly through the median The premise that circulating hormones may be forebrain bundle from the dorsal raphe nucleus of used to determine changes in central neurotransmis- the brain stem. These serotonergic pathways partici- sion is based on the role of central monoamines in pate in regulation of PRL secretion during stress, the control of hormone release from the anterior and pregnancy and lactation.[107] posterior pituitary gland. The paraventricular nucle-us of hypothalamus is the major integrating link Many studies in exercise science have monitored between the nervous and endocrine systems, with changes in peripheral hormone concentrations as an inputs from several areas of the brain governing the indication of brain neurotransmission (hormones release of pituitary hormones through the infundibu- such as PRL and ACTH). While BCAA ingestion lum stalk. Changes in the activity of serotonin, does not appear to influence PRL concentrations at  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) rest, except when large quantities (60g) are in- direct interaction, but certainly also through differ- gested,[108,109] early evidence demonstrated a clear ent receptor subtypes that might have opposite ef- relationship between serotonergic activity and plas- fects depending on the situation on the neuron (pre- ma concentrations of PRL during exercise.[110,111] or post-synaptic; located at the cell bodies, or nerve These findings resulted in the widespread use of endings etc.). Convincing evidence for a significant PRL as a peripheral index of changes in central role of serotonin in governing PRL release during serotonergic activity during exercise. However nu- prolonged exercise is poor. Therefore, we advise our tritional and pharmacological manipulation of cen- colleagues to consult the excellent review of Free- tral serotonin activity have failed to alter the PRL man et al.[107] on the regulation of PRL release response to exercise.[56,66,69] Recently, it has become before using this hormone as ‘the' indicator of brain clear that PRL release during activity is not gov- erned solely by serotonin, but through a complexinteraction between a number of neurotransmitter 4. Is ‘What We See What We Get': is the
systems.[1] Evidence also suggests that elevated Evidence for Central Fatigue
brain temperature may provide a stimulus for PRL release whilst at rest and during exercise.[112] At the pituitary level, only a few substances play It is known that serotonin and the other a role as primary neurohormones by robustly affect- monoamines have been implicated in the aetiology ing hormone secretion (e.g. dopamine), while many of numerous disease states, including depression, others can act as modulators by amplifying or di- anxiety, social phobia, schizophrenia, obsessive- minishing the effect of a primary neurohormone.[107] compulsive and panic disorders; in addition to mi- One of the major functions of and dopaminergic and graine, hypertension, pulmonary hypertension, eat- GABAergic neurons is negative-feedback regula- ing disorders, vomiting and irritable bowel syn- tion of PRL secretion to prevent an exaggerated drome, all of which are driven by one or several of PRL output during specific physiological situations the receptor types. This also implies that assigning (e.g. lactation). It is generally assumed that excitato- the central fatigue during prolonged exercise to a ry amino acids exert their effects on PRL secretion specific neurotransmitter or receptor is extremely by acting at hypothalamic targets. It has been report- unlikely. Further research is necessary to explore the ed, however, that glutamate increases PRL secre- complex functioning and interaction of the ser- tion. Other factors such as somatostatin, neuropep- otonergic and other neurotransmitter systems during tide Y, galanin, substance P, endogenous opioids also play an important role in regulating PRL secre- One should always be cautious when interpreting tion. Furthermore, it seems quite conceivable that the results of studies that used pharmacological ma- adrenergic modulation, mediated by either nora- nipulations especially as dosages and drugs used drenaline or adrenaline, plays an important role in often differ, in addition to differences in the exercise stress-induced PRL secretion.
protocol employed. The equivocal findings of these The interpretation of the hormone responses to pharmacological studies may be explained by the agents that challenge serotonin, such as agonists, complexity of the actions of the drugs employed. In antagonists and precursors, in terms of specific re- particular, these agents have varying affinities and ceptor subtypes is by no means straightforward.
specificities for the receptors they target. Further- Multiple receptor subtypes may contribute to a spe- more, the metabolites of these drugs may have dif- cific response if the agent is not specific, or if ferent effects on the reuptake sites, for example the synergistic effects of receptor stimulation are in- metabolite of fluoxetine is as potent as the ‘parent volved. Furthermore, there are several neurotrans- chemical', while paroxetine does not have a metabo- mitter interactions that will occur, not only through lite with any affinity for the site of action.[113]  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) Meeusen et al. Recent microdialysis experiments from our labo- been given to the influence of ammonia (NH3) on ratory[97,98] have demonstrated an increase in ex- tracellular hippocampal concentrations of nora- During prolonged exercise, the plasma concen- drenaline and dopamine at a relatively low bupropi- tration of NH3 increases, largely as a result of the on dose and an increase in noradrenaline and deamination of BCAA, rather than the deamination serotonin after venlafaxine administration. Al- of adenosine monophosphate to inosine monophos- though there is good evidence that acute doses of phate. This response appears to be amplified by drugs influencing central neurotransmission can reduced glycogen availability,[120,121] hyperther- transiently influence neurotransmission in ro- mia[122,123] and the ingestion of BCAA.[27,28,68] This dents,[32,97,98] the effect of these drugs on the human increase in NH3 production is one possible explana- CNS is not clear at present. Evidence from clinical tion for a failure to observe a positive effect of studies suggests that an acute administration of BCAA supplements on physical and mental per- monoamine reuptake inhibitors in humans may pro- formance, despite a good rationale for their use.
duce little change in extracellular neurotransmitter Since NH3 can readily cross the BBB, it may enter concentrations, due to a reduction in cell firing rate the CNS where excessive accumulation may have a caused by presynaptic autoreceptor-mediated feed- profound effect on cerebral function. Evidence sug- back inhibition.[30] In the light of contrasting results gests that hyperammonaemia has a marked effect of produced between animal and human studies (e.g.
cerebral blood flow, energy metabolism, astrocyte BCAA supplementation), it is worth exercising a function, synaptic transmission and the regulation of degree of caution when extrapolating the results of various neurotransmitter systems.[124] Therefore, it animal studies to humans. At present, it is not clear has been considered that exercise-induced hyperam- why these differing responses occur, but this may be monaemia could be a mediator of CNS fatigue dur- potentially explained by differences in the homeo- ing prolonged exercise.[31,118] Some support for this static regulation of central neurotransmitter homeo- hypothesis is obtained from experiments with stasis between species.
rats,[117,125] but in humans the influence of exerciseon the cerebral NH3 responses have only been 5. Are There Other Possible Factors
sparsely investigated.[2] Recently, Nybo and Responsible for Central Fatigue?
Secher[2] found that during prolonged exercise thecerebral uptake and accumulation of NH3 may pro- Fatigue, in particular central fatigue, is a complex voke fatigue, e.g. by affecting neurotransmitter me- and multifaceted phenomenon. There are several tabolism. However, further investigations of exer- other possible cerebral factors that might limit exer- cise conditions associated with marked hyperam- cise performance, all of them influencing signal monaemia are wanted to determine if the cerebral transduction, since the brain cells ‘communicate' NH3 uptake during exercise in healthy humans may through chemical substances. Not all of these rela- increase to the extent where it influences neurotrans- tionships have been explored in detail, and the com- mission and motor performance.
plexity of brain neurochemical interactions willprobably make it very difficult to construct a single In recent years, the role of central adenosine has or simple statement that covers the central fatigue been investigated through its association with caf- feine. The ergogenic effect of caffeine was original- Other neurotransmitters such as glutamate, ace- ly thought to be mediated through an increase in fatoxidation rate, thus sparing muscle glycogen.[126] tylcholine, adenosine and GABA have been tenta-tively suggested to be involved with the develop- Subsequent work has largely failed to provide con- ment of central fatigue,[114-117] but there has been too vincing support for this mechanism, leading to the few data published to date to draw any firm conclu- suggestion that the effects of caffeine supplementa- sions regarding their importance. Attention has also tion are centrally mediated. Caffeine is a potent  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) adenosine antagonist that readily crosses the BBB, cogen may be important to the development of fa- producing a marked reduction in central adenosine tigue during strenuous exercise has recently been neurotransmission. Adenosine inhibits the release of explored. The store of glycogen found in the brain is neurotransmitters, typically overlooked due to its small size (0.5–1.5g), dopamine and noradrenaline, consequently reducing but as this is a dynamic store with a high rate of arousal and spontaneous behavioural activity. The turnover, any disturbance could significantly influ- central effect of caffeine has recently been demon- ence neuronal function. A fall in the cerebral oxygen strated by Davis et al.,[116] with a marked increase in to CHO uptake ratio, determined using arterial- exercise capacity observed following an infusion of venous difference across the brain, has been report- caffeine into the brain of rodents. Interestingly, a ed following exhaustive exercise.[129] This suggests marked reduction in exercise capacity was apparent that glucose and lactate are being taken up by the when an adenosine agonist was injected centrally brain in excess of oxygen, possibly to replenish and this response was attenuated when this drug was brain glycogen stores or contribute to the de novo co-injected with caffeine.
synthesis of neurotransmitters.[2] A reduction inbrain glycogen has also been implicated in the ho- Depletion of substrates within the CNS and/or meostatic drive to sleep,[130] supporting a possible alterations in the level of certain neurotransmitters role in the fatigue process.
are potential mechanisms underlying the decline incentral activation during the sustained muscle con- There is a growing body of evidence to support traction. Maintenance of blood glucose concentra- the idea that feelings of tiredness and fatigue during tion is important for continuation of endurance exer- an illness can be triggered by the production of pro- cise at a given exercise intensity. Supplementation inflammatory cytokines, in particular interleukins of CHO results in a greater uptake of blood glucose 1β (IL-1β) and 6 (IL-6).[131,132] Communication be- by the exercising muscles, thereby preserving a high tween the periphery and the brain through IL-1β has rate of CHO oxidation late in exercise when muscle been termed ‘sickness behaviour', and is thought to glycogen levels are low.[127] The beneficial effect of be a natural homeostatic reaction to promote recov- glucose supplementation during prolonged exercise ery from infection by limiting non-essential activi- could also relate to increased (or maintained) sub- ties. It is possible that a similar response occurs strate delivery for the brain. Exercise-induced hy- following bouts of strenuous exercise and recent poglycaemia has been reported to reduce brain glu- data suggest that brain IL-1β is significantly elevat- cose uptake and overall cerebral metabolic rate,[128] ed in several cerebral regions following downhill and is associated with a marked reduction in volun- running in mice.[133] This central response was asso- tary activation during sustained muscular contrac- ciated with a marked reduction in voluntary activity tions.[64] This reduction in CNS activation is abol- in the days following the muscle damaging exercise.
ished when euglycaemia was maintained. CHO in- An energy-sensing role has been proposed for IL- gestion also attenuated losses of mental function 6.[134] Increased muscle IL-6 production during ex- observed following high-intensity intermittent exer- ercise, modulated by the muscle glycogen content, cise, mimicking that encountered during many team has been shown to stimulate lipolysis and increase sports.[70] Data from animal work suggest that glu- fat oxidation.[135] As IL-6 can readily cross the BBB, cose plays an important role in the regulation of this may act as a negative feedback mechanism to central neurotransmission and alterations in ex- the CNS contributing to the development of central tracellular glucose concentrations have been demon- fatigue.[136] An overproduction of IL-6 has also been strated to significantly influence serotonin release implicated in unexplained underperformance syn- and reuptake during exercise and recovery.[29] drome, possibly through an effect on the CNS.[132] In addition to changes in circulating blood glu- However, a number of studies have failed to find an cose, the possibility that the depletion of brain gly- association between central IL-6 release and feel-  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) Meeusen et al. ings of fatigue during prolonged exercise,[94,137-139] allowing the accumulation of unwanted substances suggesting that IL-6 may not be a major mediator of fatigue under these conditions. The possibility that Endogenous opioids are released from the brain cytokines may play a role in fatigue is a relatively during prolonged exercise.[2] An abundance of work new idea, and further work is required to understand conducted during the 1980s focused on changes incirculating β-endorphin levels and mood, with the the relationship between exercise-induced cytokine sensation known as ‘runner's high' attributed to production and the development of fatigue and/or opioids.[144] Although the endogenous opioids have recovery from strenuous exercise.
been ‘attractive' as possible candidates to influence One area of the CNS that received little attention psychological aspects during exercise, conclusions in relation to exercise is the BBB and the possibility are typically based on associations (or lack of corre- that changes in its integrity may be involved in the lation) between alterations in peripheral plasma β- fatigue process. The relative impermeability of the endorphin and psycho-physiological factors. These BBB helps to maintain a stable environment for the data should be interpreted with caution.
brain by regulating exchange between the CNS and Other cerebral metabolic, thermodynamic, circu- the extra-cerebral environment. While the BBB is latory and humoral responses could all lead to a largely resistant to changes in permeability, there disturbance of cerebral homeostasis and eventually are situations where the function of the BBB may be central fatigue. We refer to the excellent review of compromised, including infections and fever, neu- Nybo and Secher[2] for detailed information. To ronal damage and hyperthermia.[140] Either short- or date, there is evidence that because of the extreme long-term changes in the permeability of this barrier disturbance of homeostasis that occurs during pro- may allow the entry or exit of species that can affect longed exercise, peripheral and central regulatory the metabolism of the brain and thus influence a mechanisms will be stressed. However, for the mo- wide range of homeostatic mechanisms.
ment it is not possible to determine the exact regula-tion and the importance of each factor.
There is some evidence that prolonged exercise may lead to increased BBB permeability. Animal 6. Hyperthermia and Central Fatigue: Is
studies have established that the BBB can be widely There a Link with
disrupted following 30 minutes of forced swimming exercise.[141,142] Additionally, a recent human studyreported an increase in circulating serum S100β, a 6.1 Hyperthermia as a Possible proposed peripheral marker of BBB permeability, following prolonged exercise in a warm environ-ment. This response was not apparent when exercise The capacity to perform prolonged exercise is was performed in temperate conditions.[143] At pre- reduced in a warm environment. Galloway and sent, the functional consequences of changes in Maughan[145] reported that the exercise capacity of BBB permeability during exercise are not clear. A non-heat acclimated males was greatest at 11°C, small increase in brain-blood interfacing during ex- with a progressive fall in time to fatigue as ambient ercise may be desirable to facilitate the exchange of temperature was increased. Similar findings have substrates and metabolites, such as glucose and lac- been reported by subsequent work, with an inverse tate, and other substances into the CNS when cere- relationship reported between ambient temperature bral blood flow is elevated. However, a marked and exercise capacity.[146] Additionally, a 6.5% re- change in BBB permeability during exercise may duction in mean power output during a cycle time limit an individual's capacity to perform prolonged trial was reported when the ambient temperature exercise by modifying the transport kinetics of was increased from 23°C to 32°C.[147] This response neurotransmitter precursors and other metabolites or occurred despite little difference in rectal tempera-  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) ture between trials. Despite an understanding of the frequency bands. This shift towards lower frequency influence of ambient conditions on prolonged exer- α-bands is associated with feelings of tiredness and cise capacity, the underlying mechanisms behind the fatigue, and is observed during the transition from deleterious effects of heat stress are not clear at waking to sleep. In addition, a decline in cerebral blood flow has been reported during exercise withhyperthermia.[156] Perceived exertion is also signifi- As impaired substrate availability or utilisation, cantly elevated by high core temperature compared accumulation of lactate or the progressive loss of with exercise at the same intensity under normother- body fluids do not adequately explain this reduction mic conditions.[138,153] in performance when exercising in a warm environ-ment, this has lead to the suggestion that the CNS Whether exercise-induced hyperthermia influ- may be important.[148,149] Fatigue during prolonged ences neuromuscular function is not clear at present, exercise in a warm environment may coincide with with studies reporting a marked reduction[137] or the attainment of a critical core temperature, sug- little change[150,158] in force generation capacity.
gesting that there may be a thermal limit to exercise This discrepancy appears to relate to differences in performance. Nielsen et al.[150] first proposed this the duration of contraction. Nybo and Nielsen[137] concept following a comprehensive investigation of demonstrated that exercise-induced hyperthermia the effects of the physiological adaptations associat- reduces the level of voluntary activation during a ed with repeated exposure to the heat. Following a sustained maximal knee extension. The maximal period of heat acclimation, exercise capacity was contractions were performed immediately after bi- increased by 40%, with fatigue occurring at a similar cycle exercise, which in the hyperthermic trial in- oesophageal temperature of 39.7 ± 0.15°C on each creased the core temperature to 40°C and exhausted occasion. The period of acclimation appeared to the subjects after 50 minutes, whereas during the lower resting core temperature, allowing exercise control trial the core temperature stabilised at 38°C time to be extended prior to the attainment of this and exercise was maintained for 1 hour without ‘critical' temperature. This concept has been sup- exhausting the subjects. Of note, although the ported by recent findings in humans[151] and ro- hyperthermic exercise trial exhausted the subjects, it dents,[152] although Sawka et al.[13] observed that did not impair the ability of the knee extensors to around 75% of individuals appear to fatigue at a generate force, as signified by the similar force rectal temperature of 39.1°C. Premature fatigue pri- when electrical stimulation was superimposed. In or to the attainment of core body temperatures sug- addition, following a cycle protocol, force develop- gested as limiting by Nielsen et al.[150] may relate to ment during sustained handgrip contractions fol- the training status of the individual, with trained lowed a similar pattern of response as for the knee athletes seemingly able to push themselves to higher extensors, indicating that the attenuated ability to core temperatures. While it is currently unclear how activate the skeletal muscles did not depend on an elevated body temperature contributes to the de- whether the muscle group had been active or inac- velopment of fatigue, it seems possible that a critical tive during the preceding exercise bout.[154] core temperature may serve as a protective mecha- Recent studies proposed that power output during nism preventing potential damage to the body's self-paced exercise undertaken in warm ambient tissues by limiting further heat production.
conditions may be determined by a mechanism of Recent work suggests that hyperthermia may anticipatory regulation, relating to the avoidance of have a direct affect on the CNS.[137,138,153-157] Nielsen catastrophe rather than a critical limiting tempera- et al.[155] demonstrated that prolonged exercise in the ture. Tucker et al.[159] found that power output and heat was characterised by a progressive reduction in integrated electromyographic activity of the quadri- electroencephalogram activity from the prefrontal ceps muscle began to decrease early during the self- cortex, with an increase in the ratio of α to β paced exercise in the heat, but not in the cool trials  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) Meeusen et al. before the rectal temperature reached 40°C. They not alter time trial performance, cognitive perform- suggested that impaired exercise performance in the ance, mood, RPE, thermal comfort and rectal tem- heat is not the result of a limiting core temperature, perature in the heat when subjects are hypohydrated.
but occurs as part of the central regulation of skeletal In this study, hypohydration was used in order to muscle recruitment, which controls the rate of heat increase plasma osmolality and accentuate the storage, thereby preventing the development of ther- hyperthermia and cardiovascular strain. Additional- moregulatory derangement during self-paced exer- ly, ingestion of BCAA solution prior to, and during, cise in the heat. Marino et al.[160] recently examined prolonged exercise in glycogen-depleted subjects running performance and associated thermoregula- did not influence exercise capacity, rectal and skin tory responses of African and Caucasian runners in temperature, heart rate, RPE and perceived thermal cool (15°C) and in hot (35°C) conditions during an stress despite a 4-fold reduction in the plasma con- 8km time trial. African runners ran faster only in the centration ratio of f-TRP to BCAA.[68] heat despite similar thermoregulatory responses as To date, there has been little investigation of the Caucasian runners, suggesting that the larger Cauca- influence of pharmacological agents acting on the sians reduce their running speed to ensure an opti- CNS on the response to prolonged exercise in a mal rate of heat storage without developing a critical warm environment. Work conducted by Strachan et limiting core temperature. An evolutionary perspec- al.[66] recently investigated the effect of acute parox- tive suggests that physiological safeguards should etine (a SSRI) administration. While the drug in- protect individuals before catastrophic hyperther- duced a slight increase in core body temperature at mia,[161] and it seems likely that this is primarily a rest and during exercise, time to exhaustion, per- learned response developed through past exper- ceived exertion and the hormonal response to exer- iences.[162] Although these studies demonstrate an cise were not different between trials. Pitsiladis et ‘alternative' central component in the fatigue pro- al.[163] suggested that the high peripheral PRL levels cess during hyperthermia, the underlying neurobio- observed during exercise in the heat could result logical mechanisms for these responses are not clear from an increase in serotonergic neurotransmission during combined exercise and heat stress. As high-lighted previously, one should be cautious when 6.2 Is There a Link with considering PRL as an outcome measure of central Brain Neurotransmission? serotonergic activity. As evidence suggests that ele-vated brain and skin temperatures may provide a Thermoreceptors in the preoptic anterior hypo- stimulus for PRL release during exercise,[112] this thalamus (PO/AH) are responsible for regulation of suggests that HPA-hormone secretion may be linked body temperature, with changes in body temperature to the activity of the peripheral and central detected through inputs from peripheral osmorecep- thermoreceptors, rather than changes in central ser- tors and pressure receptors as well as the tempera- otonergic activity.
ture of blood flowing to the brain. As serotonergicand catecholaminergic projections innervate areas As there is limited evidence that high levels of of the hypothalamus, a change in the activity of dopaminergic activity is associated with an in- these neurons may be expected to contribute to creased tolerance to exercise in the heat,[63] we re- fatigue when core temperature is elevated.[38] cently examined the effect of a dual dopamine/ Although Mittleman et al.,[54] in a study supple- noradrenaline reuptake inhibitor on performance intemperate (18°C) and warm (30°C) conditions.[71] menting subjects BCAA during exercise, stated thatserotonin-mediated fatigue is important during exer- Subjects were able to complete a pre-loaded time cise in the heat, two recent studies have failed to trial 9% quicker in the heat following an acute dose support these findings.[67,68] Cheuvront et al.[67] re- of bupropion, but this difference between treatments ported that BCAA, when combined with CHO, did was not apparent in temperate conditions. An inter-  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) esting observation was that seven (of nine) subjects tions such as the use of anaesthesia. Ishiwata et in the heat attained core temperatures ≥40°C in the al.[167] attempted to clarify the role of serotonin in bupropion trial, compared with only two during the the PO/AH combining biotelemetry and microdial- placebo trial. In the light of these findings, it is ysis. They measured changes in core temperature possible to suggest that the action of this drug may and levels of extracellular serotonin and its metabo- dampen or override inhibitory signals arising from lite 5-HIAA in the PO/AH during cold (5°C) and the CNS to cease exercise due to hyperthermia.
heat (35°C) exposure. They also perfused fluoxetine Consequently, enabling individuals to maintain a (SSRI) and 8-OH-DPAT (5-HT1A agonist) into the high power output despite the attainment of high PO/AH. In both environmental conditions core tem- core temperatures. This response appeared to occur perature changed significantly, but no significant without any change in the subjects' perceived exer- changes were noted in extracellular levels of seroto- tion or thermal sensation, and may potentially in- nin and 5-HIAA. In addition, the perfusion of sero- crease the risk of developing heat illness. Given the tonin agents into the PO/AH did not affect core historical link between heat-related fatalities and temperature despite the fact that serotonin in the PO/ amphetamine abuse in cycling (the case of Tom AH was increased or decreased. These results sug- Simpson during the 1967 Tour de France, for exam- gest that hypothalamic serotonin may not mediate ple), manipulation of central catecholamines under acute changes in thermoregulation.
conditions of heat stress may be a potentially dan- There is one study that investigated core temper- gerous practice. As evidence for a role of serotonin ature and neurotransmitters or their metabolites in during exercise in the heat is limited[66-68] these data the hypothalamus during exercise. Hasegawa et suggest that catecholaminergic neurotransmission al.[166] reported that moderate exercise induced an may act as an important neurobiological mediator of increase in dopaminergic neural activity in the PO/ fatigue under conditions of heat stress.
AH and this was associated with a reduced body Serotonin and dopamine have been implicated in heat storage. However, the levels of serotonin and 5- the control of thermoregulation at rest[164,165] and HIAA did not change. This study suggest that tem- during exercise.[69,166] Pharmacologically induced perature homeostasis during exercise depends on increases in serotonergic activity have been demon- activation of the dopamine release in the PO/AH, strated to transiently elevate core temperature in not serotonin.
free-living rats, with the pattern of change in hypo- Recently, the functional role of PO/AH in ther- thalamic serotonin and 5-HIAA concentrations mir- moregulation during exercise has been investigated roring almost exactly the change in body tempera- using in vivo brain microdialysis.[91] Tetrodotoxin ture.[164] Strachan et al.[69] reported a marked eleva- (TTX), which blocks sodium channels, was per- tion in core temperature at rest and during exercise fused into the PO/AH to investigate whether this following pizotifen (a 5-HT2C receptor antagonist) manipulation can modify thermoregulatory func- administration, suggesting a role for the 5-HT2C tions of exercising rats. The introduction of TTX receptor in the regulation of core temperature.
into the PO/AH induced an increase in core temper- Disturbances in cerebral neurotransmitter levels, ature with a decrease in heat loss responses and an especially serotonergic activity, have long been im- increase in heat production responses during exer- plicated in central fatigue, but little work has been cise, suggesting that neurotransmission in the PO/ reported examining whether hyperthermia alters se- AH region is involved in the regulation of body rotonin levels in the brain.[161] Indeed, although temperature, especially in heat dissipation. The ex- many studies have shown that neurotransmission in act role of the specific neurotransmitters needs to be the PO/AH, the exact role of each neurotransmitter clarified since noradrenaline and dopamine but not is not established yet due to conflicting results prob- serotonin were influenced during these recent stud- ably related to experimental techniques or condi- ies,[91,167] and a recent microdialysis study also have  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) Meeusen et al. suggested that the central cholinergic and GABA- enced by peripheral factors. Furthermore, central ergic system might also be involved in thermoregu- and peripheral fatigue mutually influence each oth- lation during exercise.[89,168] Furthermore, until now er, and exercise performance is limited by a combi- there were few studies that focused on the relation- nation of factors.
ship between thermoregulation, brain neurotrans- The original central fatigue hypothesis proposed mission and exercise performance (central fatigue) that an increase in brain serotonergic activity occur- in this field. Therefore, further research is necessary ring during prolonged exercise may augment lethar- to elucidate the role of specific neurotransmitter gy and loss of drive, resulting in a reduction in systems on thermoregulation during exercise.
motor unit recruitment, and thereby affecting the This was confirmed by a recent study where a physical and mental efficiency of athletes. Since the dual dopamine/noradrenaline reuptake inhibitor publication of the serotonin hypothesis,[7,8] numer- (bupropion) was administered to rats while measur- ous theories involving accumulation or depletion of ing brain, abdominal and tail temperatures.[91] The different substances in the brain have been proposed injection of bupropion immediately increased brain to explain central fatigue. Although the theoretical and abdominal temperature, while tail temperature rationale for the ‘serotonin-fatigue hypothesis' is decreased. This change in thermoregulation was ac- clear, several seemingly well conducted studies companied by an increase in extracellular nora- have failed to support a significant role for serotonin drenaline and dopamine release in the PO/AH, while in the development of fatigue. However, it is proba- no influence was shown on serotonin. The results of bly premature to discount serotonin entirely. It has this recent study indicate that the catecholaminergic been suggested that serotonin may play an important neurotransmission in the PO/AH is responsible for role in fatigue during very long duration exercise[94] both heat accumulation and heat dissipation.
and it is distinctly possible that serotonin may act in While many investigations have contributed to a neuromodulatory role, indirectly influencing fa- our understanding of the increased thermoregulatory tigue through its action on other systems within the and metabolic demands experienced during pro- longed exercise in the heat, it is clear that the causes As brain function appears to be dependent upon of fatigue are yet to be fully understood. While early the interaction of a number of systems, it is unlikely work focused primarily on the increase in circulato- that a single neurotransmitter system is responsible ry and thermoregulatory strain, there is now a body for central fatigue. It is likely that several other of evidence to suggest that central fatigue may be mechanisms are involved, with evidence supporting accelerated when exercise is performed in a warm a role for the brain catecholamines, adenosine and NH3. A number of subtle control factors have alsobeen proposed to direct brain neurochemistry, and although little is known about the neurophysiologi-cal and psychological basis for central fatigue, it is Fatigue is determined by a complex interplay likely that the interaction of cerebral metabolic, among many factors and it is often debated whether thermodynamic and hormonal responses during pro- performance is limited by muscular, cardiovascular longed exercise will determine the delicate commu- or central factors. Central fatigue is a form of fatigue nication between the brain and the periphery. Fa- that is associated with specific alterations of CNS tigue is therefore likely to be an integrated phenom- functioning that may influence mood, the sensation enon with complex interaction among central and of effort and tolerance to pain and discomfort. It peripheral factors.
may be strange to quantify the relative importanceof central versus peripheral factors, especially be- Exercise capacity and performance is significant- cause the development of central fatigue during ly diminished when exercise is undertaken in warm prolonged maximal efforts is to a large extent influ- environmental conditions. The established peripher-  2006 Adis Data Information BV. All rights reserved.
Sports Med 2006; 36 (10) 5. Chaouloff F, Laude D, Merino D, et al. Amphetamine and al mechanisms that account for the development of alpha-methyl-p-tyrosine affect the exercise-induced imbalance fatigue when exercising in temperate conditions do between the availability of tryptophan and synthesis of seroto-nin in the brain of the rat. Neuropharmacology 1987; 26 (8): not appear to play a significant role, leading to the suggestion that the CNS is important. Evidence that 6. Heyes MP, Garnett ES, Coates G. Central dopaminergic activity hyperthermia has a profound effect on cerebral ac- influences rats ability to exercise. Life Sci 1985; 36 (7): 671-7 7. Acworth I, Nicholass J, Morgan B, et al. Effect of sustained tivity, muscle activation and perceived exertion dur- exercise on concentrations of plasma aromatic and branched- ing exercise supports this view. While it is currently chain amino acids and brain amines. Biochem Biophys Res unclear how an elevated body temperature contrib- Commun 1986; 137 (1): 149-53 8. Newsholme EA, Acworth I, Blomstrand E. Amino acids, brain utes to the development of fatigue, it seems possible neurotransmitters and a function link between muscle and that a critical core temperature may serve as a pro- brain that is important in sustained exercise. In: Benzi G,editor. Advances in myochemistry. London: John Libbey tective mechanism preventing potential damage to Eurotext, 1987: 127-33 the body by limiting further heat production. As 9. Edwards RH. Human muscle function and fatigue. Ciba Found evidence for a role of serotonin during exercise in Symp 1981; 82: 1-18 10. Bigland-Ritchie B, Woods JJ. Changes in muscle contractile the heat is limited, central catecholamines may be an properties and neural control during human muscular fatigue.
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