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0112.1M2/10/CXI03O229/S49.95/0 2010 Adis Data Infarmatlon 8V. All rights reserved.

Alterations in Central Fatigue by Pharmacological Manipulations of Neurotransmitters in Normal and High Ambient Temperature
Bart Roelands and Romain Meeusen
Department of Human Physiology and Sports Medicine, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brssel, Brussels, Belgium

Contents
Abstract 1. Fatigue: Periphery and tine CNS 1.1 Peripheral Aspects of Fatigue 1.2 Centrai Aspects of Fatigue 1.2.1 The 'Centrai Fatigue i-iypothesis' 1.2.2 Biosynthesis and Metaboiism of Serotonin, Dopamine and Noradrenaiine 2. Pharmacologicai iVIanipulations: Normai Environmentai Temperature 2.1 Serotonin 2.2 Dopamine 2.3 Noradrenaiine 2.4 Summary 3. Hyperthermia 4. Pharmacologicai iVianipuiations: High Environmentai Temperature A. 1 Effects of Catechoiamines and Serotonin on Thermai Reguiation 4.2 Effects on Performance 4.2.1 Serotonin 4.2.2 Dopamine 4.2.3 Naradrenaiine 4.2.4 Combined Dopamine/Noradrenaiine Reuptai<e inhibition 4.2.5 Caffeine 4.2.6 Summary 5. Conciusions 229 230 231 231 231 232 233 233 234 236 236 236 237 237 238 238 239 239 239 240 241 241

AbStrOCt

The scientific evidence is reviewed for the involvement of the brain monoamines serotonin, dopamine and noradrenaiine (norepinephrine) in the onset of fatigue, in both normal and high ambient temperatures. The main focus is the pharmacological manipulations used to explore the central fatigue hypothesis. The original central fatigue hypothesis emphasizes that an exercise-induced increase in serotonin is responsible for the development of fatigue. However, several pharmacological studies attempted and failed to alter exercise capacity through changes in serotonergic neurotransmission in humans, indicating that the role of serotonin is often overrated. Recent

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studies, investigating the inhibition of the reuptake of both dopamine and noradrenaline, were capable of detecting changes in performance, specifically when ambient temperature was high. Dopamine and noradrenaline are prominent in innervated areas of the hypothalamus, therefore changes in the catecholaminergic concentrations may also be expected to be involved with the regulation of body core temperature during exercise in the heat. Evidence from different studies suggests that it is very unlikely that one neurotransmitter system is responsible for the appearance of central fatigue. The exact mechanism of fatigue is not known; presumably a complex interplay between both peripheral and central factors induces fatigue. Central fatigue will be determined by the collaboration of the different neurotransmitter systems, with the most important role possibly being for the catecholamines dopamine and noradrenaline.

Every athlete will experience fatigue on a regular basis. It may be fatigue because of a short term intensive exercise such as a 200 m sprint, an eight repetitions biceps curl set at 80% of one repetition maximum, or the fatigue experienced by a triathlete after an 11-hour race. Since there are many forms of fatigue, it is obvious that there are also several definitions available. In exercise physiology, fatigue has traditionally been defined as an acute impairment of exercise performance that leads to an inability to produce maximal force output possibly due to metabolite accumulation or substrate depletion.''^ However, fatigue will not only occur at the peripheral level, since there is ample evidence that mechanisms within the CNS are also implicated in the genesis of fatigue. The purpose of this article is to review the scientific evidence for the involvement of the brain monoamines serotonin, dopamine and noradrenaline (norepinephrine) in the onset of fatigue, in both normal and high ambient temperatures. Literature incorporated in this review was collected over 5 years, when the different studies were performed in our laboratory. A literature search of PubMed and ISI Web of Knowledge with the specific key words 'dopamine', 'noradrenaline', 'serotonin', 'exercise', 'performance', 'heat', 'central fatigue' and 'thermorgulation' was performed. These studies were further selected based on their purpose, the protocol applied, the number of subjects and the use of a control group. A number of excellent reviews
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were also included and provided even more interesting articles. 1. Fatigue: Periphery and the CNS Fatigue has many definitions. Be it a 'failure to maintain the required force',Pl or an 'inability to continue working at a given exercise intensity',''' fatigue results in an acute impairment of exercise performance that includes both an increase in the perceived effort necessary to exert a desired force, and the eventual inability to produce that force.I'*' It is obvious that fatigue not only occurs at the peripheral level, but that the 'perception' of fatigue is processed at the central level,''! and that cerebral metabohsm and neurohumoral or neurotransmitter responses during exercise can be disturbed, leading to fatigue.t^' It therefore appears that many parameters affect the capacity to 'perform' during exercise and each will depend on the type of exercise, the duration of exercise and on environmental factors. The processes that lead to decrements in performance can occur at every level of the brainmuscle pathway,'^! and although the literature makes a distinction between peripheral and central fatigue, we should be aware that both pathways are possibly integrated. Readers are directed to the work of St Clair Gibson et al.,'^' Marino,'^' Noakes et al.'^' and others on the perception of effort and possible integration of central and peripheral signals during exercise. This model describes a complex and intelligent
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regulatory system that integrates peripheral and central elements of fatigue into a teleoanticipatory pacing system, which seeks to alter exercise intensity to maintain homeostasis at all times to prevent the catastrophic cessation of exercise. For the purpose of this review, central fatigue is denned as fatigue originating from the CNS, There is a strong link between alterations in neurotransmitters and neuromodulators and an individual's mood; this implies that an increased sense of effort and a diminished drive to continue exercise result in centrally mediated fatigue, 1.1 Peripheral Aspects of Fatigue Much research has focused on the peripheral aspects of fatigue, induced by the occurrence of a 'metabolic end-point',['1 An important cause of peripheral fatigue is depletion of energy stored in the working muscles. Studies have shown that during prolonged exercise, the rate of adenosine triphosphate (ATP) utilization exceeds the rate of ATP synthesis,'"! Jhis might be due in part to decreased levels of creatine phosphate,''^' although Baldwin et al,''-'! \ not find these specific changes during prolonged exercise. As substrate availability is important, the depletion of muscle glycogen is often linked with muscle fatigue. At a certain point during prolonged exercise there will be an inability to maintain a sufficient rate of ATP resynthesis, secondary to reduced availability of pyruvate and key metabohc intermediates with the appearance of fatigue,t''*' Besides depletion of energy sources, the accumulation of metabolic by-products - such as lactate and hydrogen ions after breakdown of glycogen, and glucose and ammonia after the breakdown of both ATP and amino acids''^' - have also been implicated in peripheral fatigue. During exercise without adequate fiuid replacement, dehydration can occur. Even small decreases in body fiuid can alter cardiovascular function and can consequently impair performance,''^1 The magnitude of this effect will increase when exercise is performed in higher environmental temperatures,''^' If sweat loss during exercise is increased, the body has a smaller amount of blood volume to contribute to the
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sweat output; therefore, over time, blood fiow to the skin is reduced, sweat output is decreased and the ability to dissipate heat is inhibited. This results in increased thermal strain, which may elicit fatigue by impairing voluntary activation of the

1,2 Central Aspects of Fatigue Much research has been focused on the involvement of the motor pathways in fatigue, Neuromuscular fatigue occurs when a progressive exercise-induced failure of voluntary activation of the muscle exists together with a gradual failure to drive motor neurons, Taylor and Gandevia'^^' state that neuromuscular fatigue can be demonstrated by an increase in the increment of force evoked by nerve stimulation during a maximal voluntary contraction,'-^^l If extra force can be evoked by stimulating the motor neurons (superimposed twitch), central fatigue possibly takes place due to supraspinal mechanisms,P' For an excellent review on this topic see the work by Taylor and Gandevia,'^"''^'' Brain neurotransmitter activity has not only been implicated in the regulation of cardiovascular'-^-^'-^-'i and endocrine'^'*'^^' responses during exercise; neurotransmitters and especially the central monoamines are also strong candidates as neurochemical supports for central fatigueinducing effects of exercise,
1.2.1 The 'Central Fatigue Hypottiesis'

The monoamines serotonin, dopamine and noradrenaline play a key role in signal transduction between neurons, and exercise-induced changes in the concentrations of these neurotransmitters (especially serotonin and dopamine) have been linked to central fatigue, Romanowski and Grabiec'^^' related serotonin, while Heyes'^''! linked dopamine to a possible centrally mediated fatigue. Initiated by Acworth et al,,'^^' Newsholme and his co-workers'^'^ developed the first hypothesis implicating changes in central neurotransmission to explain fatigue, i,e, the 'central fatigue hypothesis'. This hypothesis is based on disturbances in brain serotonin concentrations, as this neurotransmitter is
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involved in changes in sleep-wakefulness, emotion, sleep, appetite, the hypothalamic-pituitary axis and numerous physiological functions.!'"] During exercise, the entry of tryptophan, a precursor of serotonin, into the CNS through the blood-brain barrier is favoured by increased muscle use of branched-chain amino acids and elevated plasma fatty acids, as this elevates the ratio of unbound tryptophan to branched-chain amino acids. This increases the amount of tryptophan crossing the blood-brain barrier, consequently leading to higher serotonin concentrations in the The hypothesis put forward by Newsholme et al.P^ has been challenged by several research groups who tried to manipulate performance and delay fatigue by different nutritional and pharmacological interventions, both in humans and in animals. The effects of the nutritional manipulations are not the main focus of this review and will not be discussed in detail (for a review on this topic see Meeusen et al.f'l). Table I (human, normal ambient temperature), table II (human, high ambient temperature) and table III (animal) give an overview of studies that 'pharmacologically' tried to manipulate brain neurotransmission in the search for mechanisms of fatigue induced by changes in the synthesis and metabolism of central monoamines.
1.2.2 Biosynthesis and Metabolism ot Serotonin, Dopamine and Noradrenaline

This review focuses on pharmacological manipulations used to explore the central fatigue hypothesis. Most studies employing pharmacological substances aim at influencing different neurotransmitters and amino acids that have been related to central fatigue. The most important are serotonin, dopamine, noradrenaline, tryptophan, branched-chain amino acids, yaminobutyric-acid, glutamate, acetylcholine and adenosine. This review specifically focuses on three monoamines: serotonin, dopamine and noradrenaline. Serotonin-containing neurons are present in the cells located along the midline of the brainstem. They are mostly clustered in the raphe nuclei and their axons innervate nearly every region of the
2010 Adis Data intarmatian BV. All rights reserved.

^l The synthesis of serotonin requires two enzymatic steps. First, the amino acid precursor tryptophan is hydroxylized by tryptophan hydroxylase to L-5-hydroxytriptophan, and second, it is decarboxylated to serotonin. Metabolization occurs via aldehyde dehydrogenase and monoamine oxidase to 5-hydroxyindoleacetic acid.'''^' Increases in serotonin are presumed to play an important role in various behavioural functions, such as increased feelings of tiredness, fatigue and pain, and decreases in the level of arousal.t^^' Dopaminergic cells are primarily located in the mesencephalon, diencephalon and telencephalon. The main pathways include the nigrostriatal tractus, ventral mesostriatal pathway and tubero-infundibular system.(^^^ Neurons that synthesize noradrenaline are restricted to the pontine and medullary tegmental region, with the locus coeruleus being the most important noradrenaline nucleus.t^^l Tyrosine hydroxylase is converted to L-3,4-dihydroxyphenylalanine (L-DOPA) by tyrosine hydroxylase. DOPA is then decarboxylated to dopamine by DOPA decarboxylase. Dopamine is implicated in increases of arousal, motivation, reinforcement, reward, the control of motor behaviour and mechanisms of addiction,'^^' and can be reloaded in the synaptic vesicles for reuse. Dopamine is metabolized by monoamine oxidase to 3,4-dihydroxyphenylacetic acid, which is further destroyed by catechol-0-methyltransferase to homovanillic acid, or can be converted into noradrenaline by dopamine--hydroxylase. The catabolism of noradrenaline happens via monoamine oxidase and catechol-0-transferase. The main metabohte is 3-methoxy-4-hydroxypheny lethylene-glycol .'^^1 In their excellent review, Davis and Bailey^'*! stated that not only increases in serotonin but an interaction between serotonin/dopamine would influence CNS fatigue, with a low ratio favouring improved performance and a high ratio decreasing motivation and augmenting lethargy, consequently decreasing performance.t'*! The scientific evidence for the involvement of the brain monoamines serotonin, dopamine and noradrenaline in fatigue during prolonged exercise, in both normal and high ambient temperatures is reviewed in the following sections.
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Table I. Pharmacological manipulations of central neurotransmission In humans In normal ambient temperature study (year) Wilson and Maugan^"' (1992) Struderetal.'l(1998) Davis et al.'=2l (1993) Meeusenetal.l^l(2001) PariseetaLi^iMaooi) Subjects (no. of men) 7 10 6 8 11 12 11 8 13 Drug Paroxetine Paroxetine Fluoxetine Fluoxetine Fluoxetine Fluoxetine CItalopram Pizotifen Buspirone Details SRI SRI SRI SRI SRI SRI SRI Serotonin 5-HT2C antagonist 5-HT, A agonist, dopamine D2 antagonist
5-HT2A/2C

Exercise protocol Cycling at 70% V02max exh Cycling 2 mmol/L lactate exh Cycling at 70% VO2max exh; incremental test to exh 90minTT Wingate+ 80% V02max exh Wingate+ 90% V02n,ax exh Cycling 60 min 55 Running at 70% V02max exh Cycling at 80%VO2maxexh

Amb T 18

Performance

I i
I

18

4-

4-

Roelands et al.i35i (2009) Pannier et al.P^i (1995) Marvin et al.13^1 (1997)

18
4-

I
18 18 18 18 18 18 18

Meeusenetal.P(1997) Piacentini et al.Pai (2002) Piacentini et al.'""! (2002) Roelands et al.!"" (2008) Piacentini et al.l'^' (2004) Watson et al.f^i (2005) Meeusenetal.i3(1997) Swart et al.'""! (2008) Roelands et al.i''=) (2008) Jacobs and Belli" (2004)

7 7 7 9 8 8

Ritanserin Venlafaxine Reboxetine Reboxetine Buproplon Buproplon L-Dopa

Cycling at 65% VO2max exh 90minTr 90minTT Cycling 60 min 55 90minTT Cycling 60 min 55 Cycling at 65% VO2max exh Cycling at fixed RPE of 16 Cycling 60 min 55 Cycling at 85% V02max exh

antagonist SNRI NRI NRI Dopamine/NRI Dopamine/NRI Dopamine precursor Dopamine reuptake inhibitor Dopamine reuptake inhibitor a,-Adrenergic agonist

i *-

7 Methylphenldate 16 Methylphenidate 8 Modafinll 15

18
4-

5-HT=5-hydroxytryptamine; Amb T = ambient temperature; exh = exhaustion; L-Dopa = L-3,4-dihydroxyphenylalanine; NRI = noradrenaline reuptake inhibitor; RPE = ratings of perceived exertion; SNRI = serotonin/noradrenaline reuptake inhibitor; SRI = serotonin reuptake inhibitor; TT = time trial; VO2mox = ''is'<imal oxygen uptake; Wm3, = maximal wattage; T indicates significant increase; -> indicates no difference; I indicates significant decrease.

2. Pharmacological Manipulations: Normal Environmentai Temperature In a previous paper we have already discussed several of the existing studies.t'l Therefore, in this review we only briefly present the most relevant papers and review new fmdings from research during the last 3 years, with special focus on the pharmacological manipulations used to unravel the mechanism of'central fatigue'.
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2.1 Serotonin In rats, Bailey and co-workers'^''"^^^ provided convincing evidence for a role of serotonin in the onset of fatigue. By using serotonin agonists, they showed that increased central serotonin activity decreased performance, while administration ofa serotonin 5-HT|c/2 receptor antagonist (decreasing serotonin activity) led to performance improvement.
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Table II. Pharmacoiogical manipuiations of centrai neurotransmission in humans in high ambient temperature study (year) Strachan et ai.i'"'! (2004) Roeiands et ai.P=l (2009) Strachan et ai.i"! (2005) Bridge et ai.i"^! (2003) Subjects 8m 11 m 6 m; 1 f 12m Drug Paroxetine Citaiopram Pizotifen Buspirone Detaiis SRI SRi 5-HT2C antagonist 5-iHT,A receptor agonist; dopamine D2 antagonist Dopamine reuptake inhibitor Dopamine/NRi Dopamine/NRi NRi Exercise protocoi Cyciing at 60%
VOamax exh

Amb T (C) 32 30 35.5 35

Performance

Cyciing 60 min 55 Cyciing 40 km TT Cyciing at 73%

VOjmax exh

Roeiands et al.f^l (2008) Watson et ai.H^l (2005) Roeiands et ai.i^"! (2009) Roeiands et ai.'"'! (2008)

8m 8m 8m 9m

iVIethyiphenidate Bupropion Chronic bupropion Reboxetine

Cycling 60 min 55 Wmax+30minTT Cyciing 60 min 55 Cyciing 60 min 55 Cyciing 60 min 55

30 30 30 30

5-HT=5-hydroxytryptamine ; A m b lr=ambient temperature; exh = exhaustion; f=femaie; m = maie; NRI = noradrenaiine reuptake inhibitor; SRI = serotonin reuptake inhibitor; TT=time trial; V02max = maximai oxygen uptake; W^, = maximai wattage; T indicates significant increase; <-> indicates no difference; I indicates significant decrease.

From the literature it appears that results in humans are not that conclusive. Wilson and Maughan,Pi Marvin et al.'^^J and Struder et al.'-"' reported a shorter exercise time to exhaustion compared with placebo. Struder and Weicker'^'^ suggested, however, that the reduced exercise performance capacity might have been caused by differences in the regulatory function of serotonin rather than the increase in serotonin activity. The lack of response of prolactin after serotonin reuptake inhibition supported this statement.f^'l Furthermore, endurance-trained athletes might also have developed mechanisms to compensate for excessive increases of brain serotonin.'^^1 Other studies were unable to detect any differences in performance after serotonin reuptake inhibition.[^^'^^'-^^l In a recently developed protocol, Roeiands et al.'^^^ administered citaiopram, a selective serotonin reuptake inhibitor, to subjects. In 18C ambient temperature, no differences in performances were observed for time-trial time. The contrasting findings in the literature probably result from the complexity of the serotonin neurotransmitter system, as many different receptors and receptor subtypes have been identified, each with different functions and inter 2010 Adis Data Infarmation BV. All rights reserved.

actions (for a review see Zifa and Fillion'!). However, this recent study and previous findings suggest that serotonin is not the key factor in the development of central fatigue but may play a role in combination with other neurotransmitter systems, f* "! 2.2 Dopamine Animal studies have shown that when rats stop exercising because of fatigue, dopamine concentrations are low due to an interaction with serotonin,[^''J and the ratio between serotonin and dopamine has been hypothesized to influence central fatigue.'''^ Gerald'^^^ administered amphetamines, potent catecholamine releasers to rats, and found significant increases in running time until exhaustion. Heyes et al.P^' infused rats with apomorphine (a dopamine agonist) and found a clear increase in the running time until exhaustion. After destruction of dopamine neurons, apomorphine was capable of restoring exercise capacity. In humans, Meeusen et al.'^^l were not able to induce performance differences after supplementation with a dopamine precursor; L-3,4-dihydroxyphenylalanine (L-Dopa). Piacentini et al.l''^^
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influenced catecholaminergic transmission by administering a dual dopamine/noradrenaline reuptake inhibitor (bupropion). When bupropion or placebo were both administered, respectively, subjects finished a predetermined amount of work in the same amount of time (approximately

90 minutes). Animal studies showed that acute intraperitoneal bupropion injection produced increases in brain and core temperature and a decrease in tail temperature (heat loss mechanism) through an increase in noradrenaline and dopamine in the preoptic area and anterior hypothalamus

Table III. Pharmacological manipulations of central neurotransmission in animals in normal and high ambient temperature Study (year) Subjects; no. SD rat; 64 maies Rats Wistar rat maies Wistar rat; 8 Wistar rat; 36 Wistar rat; 8 per group SD rat; 10 males SD rat; 57 males Drug Serotonin Details NA Exercise protocol Crossing tilt cage; activity measured Open field activity+treadmill Spontaneous running activity RTTE (20 m/min; 5% incline) RTTE (20 m/min; 5% incline) RTTE (20 m/min; 5% incline) RTTE (different speeds) Treadmill running (36 m/min) Performance

Normal ambient temperature Jacobs and Eubankst^'l (1974) Hillegaart et al.i^^i (1989) Wilckens et a l . ' " ' (1992) Bailey et al.'^' (1992) Baiiey et al.'==' (1993) Bailey et al.'^^' (1993) GeraldP^'(1978) Heyes et a l . ' " ' (1985)

8-OHDPAT m-chl-piperazine; DOI; quipazine m-chi-piperazine Quipazine; LY 53857 Quipazine; LY 53857 (+)-Amphetamine 6-OH dopamine lesion; apomorphine; clonidine (+)-Amphetamine; pargyline; a-methylp-tyrosin; haioperidol Methamphetamine

5-HT,A agonist 5-HTic agonist; 5-HT2 agonist; serotonin agonist 5-HT,c agonist Serotonin agonist; 5-HTic and 5-HT2 antagonist Serotonin agonist; 5-HTic and 5-HT2 antagonist Release catecholamine Dopamine agonist; 02 agonist

i
I
Quipazine; -I LY 53857; t Quipazine; i 32% LY 53857; T 26%

T
6-OH dopamine; i apomorphine; clonidine; -

Chaouioff et ai.'=8' (1987)

Wistar rat; 5 per group males

Release catecholamine monoamine oxidase B inhibitor; inhibitor catecholamine synthesis; dopamine antagonist Dopamine reuptake inhibitor and neurotoxin

60 min treadmill (20 m/min; 5% incline)

Kalinski et al.'^^' (2001)

Mice; 15 maies

1 ;4x increasing speed; 2;RTTE (35 m/min) Forced swim test RTTE (15 m/min; 5% incline) RTTE (20 m/min; 5% incline) 120 min running (10 m/min)

Connor et al.'^l (1999) Lima et ai.'^" (1998) Rodrigues et al.i^^i (2004) Hasegawa et al.'^2' (2005)

SD rat; 7-8 Wistar rat; 27

Reboxetine Atropine

NRI Antagonist central and peripheral muscarinic acetylcholine receptors Acetylcholinesterase inhibitor Sodium channel blocker

I I <-.
i-.

Wistar rat; 8 Wistar rat; 2

Physostigmine Tetrodotoxin

High ambient temperature RTTE (26 m/min) Dopamine/NRI Bupropion Wistar rat; 8 Hasegawa et al.l^' (2008) 5-HT=5-hydroxytryptamine; 5-HTTP=5-hydroxytryptophan; 6-OH=6-hydroxydopamine; 8-OHDPAT=8-hydroxy-N,N-dipropyl-2-aminotetralin; DOI=2,5-dimethoxy-4-lodoamphetamine; m-chl = m-chlorophenyl; NA=not available; NRI = Noradrenaline reuptake inhibitor; RTTE = running time to exhaustion; SD = Sprague-Dawley; t indicates significant increase; <> indicates no difference; -L indicates significant decrease. -

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( ) ' ] and that neurotransmitter concentrations increased in the hippocampus,f''^^ A recent human study from our laboratory''*^] used the same drug, bupropion, Catecholaminergic manipulation did not induce a difference in time-trial time at normal environmental temperature, but compared with placebo, core temperature was significantly elevated during the time trial without any changes in the subjects' ratings of perceived exertion (RPE) and thermal stress scale,''*^] In a recent study by Roelands et al,,t''^l methylphenidate, an amphetamine-like stimulant widely administered to patients diagnosed with attention deficit hyperactivity disorder, was given to subjects. Treatment in normal ambient temperature did not induce any significant changes in performance and led to a nonsignificant rise in core temperature. The authors observed no change in RPE and thermal stress scale. As amphetamines are known for their performance-enhancing effects,'^^'^^' the reason for the lack of ergogenic effects in humans after dopamine manipulation in normal ambient temperature is not yet clear. Possibly, the influence of dopamine might not be strong enough in normal environmental temperatures,'"*^] However, the result found by Roelands et al,'"*^] is in contrast with fmdings by Swart et al,,''*'*' who observed subjects exercising at a fixed RPE after methylphenidate administration. Swart et al.''*'*] concluded that endurance performance is not only 'limited' by mechanical failure of the exercising muscles; rather, performance during prolonged endurance exercise under normal conditions is highly regulated by the CNS,
2,3 Noradrenaline

while Piacentini et al,'"*"! showed a trend towards a decrease in performance after acute administration of reboxetine (8mg), a noradrenaline reuptake inhibitor. The authors found a 'non-significant' 5-minute difference in a 90-minute time trial when compared with placebo, Roelands et al.'""' administered reboxetine (16 mg) and found a 10% slower timetrial performance. This decrease in performance was unexpected; however, it is well known that noradrenaline neurons modulate the serotonin neurotransmitter system via excitatory a|receptors. The authors found a trend towards lower core temperatures, and subjects' thermal stress scale scores were lower after reboxetine administration, indicating a hypothermie effect of noradrenahne reuptake inhibition. This effect was previously reported in animal studgg[75-77] ^j^ jg mediated by ot2-noradrenergic receptors in the PO/AH.'^^J
2,4 Summary

Less research has been performed on the role of noradrenaline in the onset of central fatigue. As noradrenaline is implicated in the control of level of arousal, consciousness and reward mechanisms in the brain, one would expect that noradrenaline reuptake inhibition leads to a delay in fatigue,'^"*] Results from Piacentini et al,,'^'] administering a serotonin/ noradrenaline reuptake inhibitor (venlafaxine), show, however, no difference in performance.
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To summarize, animal studies that manipulated neurotransmitter systems through the administration of drugs, showed that fatigue can be ehcited in normothermia, indicating an important role for serotonin and dopamine neurotransmission. However, in humans there is less clarity. Most evidence suggests that serotonin and dopamine are involved in central fatigue, but might not individually be able to alter fatigue. The noradrenahne neurotransmitter system has a negative influence on performance in normal ambient temperature. As it seems difficult to postpone fatigue in normothermia, in recent years there has been an increased interest in the role of hyperthermia and the link with pharmacological agents acting on the CNS during prolonged exercise,
3. Hyperthermia

In both heat and cold, homeothermic animals utilize autonomie and behavioural responses to regulate their body temperature. These responses are better known as thermorgulation,'^'l Mechanisms by which humans lose heat are well
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described and include dilatation of the skin vessels, causing the warm blood from the body core to flow to the skin with sweating to facilitate evaporative heat loss. The hypothalamus is seen as the 'thermoregulatory centre' of the brain, and more specifically the PO/AH is thought to be the most important region, as it contains both coldsensitive and hot-sensitive neurons.'^'J The PO/AH receives input from both peripheral and central thermoreceptors, and initiates appropriate heat loss or heat production responses.'^''l During exercise we are no longer able to redistribute the same amount of blood from the body core to the skin, as the working muscles also demand an increased amount of blood.'^'''^ The logical outcome is a rise in core temperature, inducing hyperthermia. The consequences are increases in the physiological strain on the body, and a severely impaired exercise capacity. Decreases in performance are specifically reported when exercise is undertaken in high ambient temperatures. Parkin et al.'^"' and Galloway and Maughan'^'l showed that exercise time to fatigue was significantly lower when exercise was undertaken in the heat, compared with normal and low ambient temperature. Mechanisms that cause this detrimental effect on performance were assumed to be associated with muscular and peripheral factors; however, these are not altered to such an extent that it would explain the diminished endurance during prolonged exercise in the heat.'^' Muscle glycogen stores are far from depleted, muscle and blood lactate concentrations are not elevated to levels normally associated with fatigue, and potassium release does not explain the hyperthermia-induced fatigue either.t^^"^^! Brck and Olschewski'***! suggested that performance in the heat is primarily regulated by a diminished drive from the CNS. This finding was later confirmed in studies by Nielsen et al.'^^'^'*' An excellent review by Cheung'^^^ describes how over the past decade two major paradigms have been proposed for how hyperthermia may contribute to voluntary fatigue during prolonged exercise in the heat. The first paradigm suggests that exhaustion occurs upon the attainment of a critical core and brain temperature, serving as a protective mechanism and preventing po 2010 Adls Data Information BV. All rights reserved.

tential damage to body tissue by limiting further heat production.['^^^^^^^' This view has been supported by the observation that trained subjects, starting with different core temperatures, stop exercising at similar body core temperatures ~40C.''' Brain temperature is a physiological parameter that is determined primarily by neural metabolism, and regulated by cerebral blood flow, which serves as a body-coupled heatexchanger system penetrating all brain structures.'^' Nybo and Scher'^' reported that cerebral blood fiow is of utmost importance with regard to the cooling of the brain and is a safety mechanism to prevent a high level of heat storage and excessive hyperthermia, thus protecting the brain from thermal damage.'*''' The second paradigm states that complex feed-forward and feedback mechanisms regulate fatigue. In this way, humans should be able to anticipate the intensity of heat stress that they will be or are exposed to, and would seek to regulate their workload accordingly to minimize heat storage.'''-^'' This view has been supported by the finding that subjects reduce their workload early in a maximal 20 km time trial in the heat, prior to any increase in core temperature relative to normal ambient conditions. Serotonin, dopamine and noradrenaline have all been implicated in the control of thermorgulation and are thought to mediate thermoregulatory responses,'''^' certainly since their neurons innervate areas of the hypothalamus, among which are also the PO/AH. It can be expected that a shift in the concentrations of these neurotransmitters contributes to changes in thermal regulation and consequently to fatigue, specifically when exercise is undertaken in hot environmental conditions. However, very little work has been reported on this potential mechanism (tables II and III). 4. Pharmacological Manipulations: High Environmental Temperature 4.1 Effects of Catecholamines and Serotonin on Thermal Regulation The effects of brain catecholamines and serotonin on thermal regulation have been studied
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in humans and animals. Noradrenaline microdialyzed in the PO/AH of different animal species evokes a fall in core temperature, a reaction mediated by a2-adrenoceptors.[^^"^^l On the other hand, studies that agonized ocpadrenoceptors found rapid rises in core temperature.''^''l Local application of serotonin in the PO/AH was reported to alter thermosensitive neurons,'^"*' and studies reported both a rise'^^' and a fall''^' of body temperature. Clark and Lipton'^^^ reviewed different responses of core temperature after micro-injection of serotonin into the PO/AH and concluded that the role of serotonin in the PO/AH in thermorgulation is obscure.'^^1 Hasegawa et al.^^'^ were able to show from a microdialysis study in rats that dopamine is important in the control of core temperature by modulating metabolic levels during exercise, while Ishiwata et al.I"'^' showed that y-aminobutyric acid is an important inhibitor of heat production in high environmental temperatures. Recently, perfusion of tetrodotoxin (a poison of the Japanese puffer fish that acts as a sodium channel blocker and is widely used for blockage of neurotransmission in specific brain regions) into the median raphe nucleus of rats induced considerable decreases in core temperature at 5C and 23C but not at 35C.t''' In contrast, when tetrodotoxin was microdialyzed in the PO/AH, it induced hyperthermia.t'"^^ Hasegawa et al.'^^J reported no change in the exercise behaviour of rats after injecting tetrodotoxin in the PO/AH via microdialysis. Tetrodotoxin did induce an increase in body core temperature, with a decrease in heat loss responses and an increase in heat production.t^^J From these and previous animal studiest^^'^^-'^''^"''^ it seems fair to suggest that neurotransmission in the PO/AH region is inr volved in the regulation of body temperature during exercise and that both the catecholamines and serotonin can influence core temperature. Another key factor in the regulation of the internal body temperature is the environmental thermal condition. There have been interesting studies proving the effect of changes in environmental conditions to be imperative in the control of core temperature through the manipulation of neurotransmitter concentrations. Ampheta 2010 Adis Data Information BV. All rights reserved.

mine has been shown to cause hyperthermia at temperatures of 20-37C but hypothermia at 4-14C.['^l Methamphetamine has shown the same effects.'"''*^ Malberg and Seidenl'^l showed that small changes in ambient temperature (2C) can produce changes in the thermal response to 3,4-methylene dioxymethamphetamine. At 20C, 3,4-methylene dioxymethamphetamine had a hypothermie effect, without significant changes in serotonin concentration, while at 30C there was a clear hyperthermic effect, coinciding with a decrease in serotonin. In a recent study, Myles et al.'"'^^ reported that methamphetamine did not change core temperature at 24C, but there was a hypothermie effect at 20C and a hyperthermic effect at 28C. These results indicate that ambient conditions play an important role in the regulation of body core temperature.
4.2 Effects on Performance

Substrate availability in normothermia can, at least in part, account for the fatigue that occurs during prolonged exercise.['^J In the heat, it is clear that giycogen availability does not limit exercise capacity, and there is no clearly defined mechanism by which hyperthermia causes the decision to stop exercising.''"^^ Since serotonin, dopamine and noradrenaline have all been implicated in thermorgulation and central fatigue, researchers focused their attention towards the link between both by using pharmacological substances to disturb normal neurotransmission.
4.2.1 Serotonin

Strachan and co-workersf'*^' examined the effects of the serotonin reuptake inhibitor paroxetine at 32C in a time-to-exhaustion trial. The authors found no evidence for detrimental effects of serotonin on exercise capacity, nor were there any differences in the subjects' RPE between the placebo and drug trial. Core temperature was very slightly increased by paroxetine, suggesting that it acts as a postsynaptic serotonin agonist.t'^^ This increase in core temperature might have been too small to evoke any negative effects on performance. The authors therefore concluded that the administration of paroxetine did
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not significantly influence thermoregulatory factors that may limit performance.I'*^^ In a follow-up study,'"*^^ the role of serotonin was further explored during exercise in the heat. Pizotifen, a selective 5-HT2C receptor antagonist, was administered in order to examine whether blockade of 5-HT2C receptors exacerbates the thermal response and limits exercise performance in a 40 km time trial. Rectal temperature was increased by pizotifen, thereby confirming the results of a rodent studyt' '"^ that the 5-HT2 receptor family has a role in thermorgulation. However, the higher rectal temperatures did not induce any change in performance.'''^^ The lack of effect on performance confirms the results of Meeusen et al.,P^l who found no change in time to exhaustion after ritanserin (5-HT2A/2C antagonist) administration at normal ambient temperature.
4.2.2 Dopamine

changes in the thermal stress scale scores, and although the subjects' heart rate and power output were higher, RPE was identical compared with placebo. Thus, it appears that mechanisms existing in the body to prevent harmful effects are dampened or overridden by the administration of a dopamine reuptake inhibitor, even at the low dose (20 mg, one-third of the maximal daily dose) administered. This prompted the authors to suggest there is a potential danger for the development of heat il
4.2.3 Noradrenaiine

Two studies provided evidence for an important role of dopamine in delaying fatigue and increasing core temperature combined with exercise in the heat. Bridge and co-workers''"^ administered buspirone, a drug that acts on 5 - H T I A and dopamine, to subjects exercising at 35C. The authors concluded that there is evidence that high levels of dopamine activity in the hypothalamus are associated with an increased tolerance to exercise in the heat. We studied the effects of acute dopamine reuptake inhibition in the heat.''*^! The results of this study indicate a strong ergogenic effect of methylphenidate at 30C. A time trial was completed >7 minutes (16%) faster when dopamine reuptake was inhibited. Core temperature during the methylphenidate trial was significantly increased at rest, presumably due to the increased dopamine activity in combination with the heat, as also shown in other stujjgg [105,106] During time trials it is presumed that a significantly greater metabolic heat production in the methylphenidate trials results from the increased drive and motivation due to the dopamine reuptake inhibition. Interestingly, in the methylphenidate trial, average core temperature was 40C, while in the placebo trial only one subject reached this temperature. Despite reaching these high core temperatures there were no
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A completely different effect was observed for noradrenaiine reuptake inhibition (with reboxetine).'"'^ Performance during time trials at 30C with administration of reboxetine was 8 minutes (20%) slower compared with placebo trials conducted at this temperature. As noradrenaiine is implicated in arousal and reward mechanisms, a better performance would have been expected rather than the 20% decrease. In fact, the present result is not that surprising, as Piacentini et al.f''' had already found a trend towards a decrease in performance with only half the dose administered. Core temperatures tended to be lower after reboxetine supplementation and subjects felt significantly colder. This confirms results from animal studies.'^^'^^l Quan et al.'^^ showed that this effect is mediated by a2-noradrenergic receptors in the PO/AH. On the other hand, heart rates were higher after noradrenaiine reuptake inhibition, which can be explained by a combination of both central and peripheral factors. Augmented noradrenaiine concentrations are able to increase sympathomimetic activity, but it has also been hypothesized that the noradrenaiine reuptake inhibition augments central noradrenaiine inhibition in the parasympathetic nuclei, causing lower cardiac parasympathetic tone and an increase in heart rate.'"'!
4.2.4 Combined Dopaminel Noradrenaiine Reuptaice inhibition

Acute dopamine reuptake inhibition has a strong ergogenic effect, while acute noradrenaiine reuptake inhibition has the opposite effect.f'""''^' Results from these studies can be applied to the results of the acute bupropion
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Study. The literature suggests that bupropion shows a 2.5-fold selectivity for dopamine versus noradrenaline, while no changes in serotonin were reported.I^'*^ The European Agency for the Evaluation of Medicinal Products^' ' '^ states that after bupropion administration, peak plasma concentrations are reached after 2-3 hours, while for the major metabolite, hydroxybupropion which acts on the noradrenaline transporter peak plasma concentrations are only reached after 6 hours. This means that bupropion first exerts its effects via dopamine pathways, while later there is a switch towards higher involvement of noradrenaline. As dopamine is known to have strong ergogenic effects when exercise is undertaken in high ambient temperature, this mechanism of action explains how bupropion improves performance and increases core temperature after acute administration. The results of the acute bupropion study in humans'''^^ were further explored in rats.'^"*^ The authors examined the effect of bupropion in rats exercising in both normal and high ambient temperature. Microdiaiysis studies in rats have shown that acute administration of bupropion affects dopamine release in the striatum and nucleus accumbens,'"^! and affects hippocampal dopamine, noradrenaline and serotonin release.f^^' Running time until exhaustion was significantly influenced by ambient temperature, thereby confirming earlier studies in humans.'^'^'l Brain and core temperature at exhaustion were significantly higher in the bupropion trial in the heat compared with the warm placebo trial. The higher core temperature was also observed after bupropion injection in freely moving rats,'""! while no differences in tail temperature were obvious between trials. These results are in line with those previously observed in humanst"*^! and indicate the potential performance-enhancing effects of this drug through its dopaminergic action. Bupropion is widely prescribed (40 million clinical-use exposures'"^') and is to be taken in a chronic manner. With regard to the impact of an acute dose, it was imperative to investigate the effects of chronic manipulation with the same drug.'^^l Results from this study were less pronounced. Core temperature
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was significantly higher compared with a placebo, but only reached an average of 39.6C. Performance was not influenced by the chronic drug treatment (10 days). The reason for the diminished action after chronic bupropion administration will probably be linked to a central neurotransmitter homeostasis.t^"' After approximately 7 days, bupropion and its metabolites reach steady-state levels.'"^^ Peak plasma levels with chronic administration are similar compared with levels reached after acute dosing, while for hydroxybupropion there is a 4-fold increase at steady-state compared with acute administration.''"' Logically, the concentration of hydroxybupropion gains importance as the ratio bupropion/hydroxybupropion is firmly decreased, indicating an increase in noradrenaline influence. Studies by Piacentini et al.''*''^ (5 minutes) and Roelands et al.''"' showed slower performances after increased noradrenaline neurotransmission (8 minutes), causing the different result when compared with acute bupropion administration.'''^^ Furthermore, Leamed-Coughlin et al.'' ''*' showed that after 11 days of bupropion there was only a low occupancy of the dopamine transporter. Serotonin, dopamine and noradrenaline are used in many therapeutic agents: sometimes combined, sometimes separately. Most antidepressants affect serotonin and/or noradrenaline and to a lesser extent dopamine, as there is evidence that drugs acting exclusively on dopamine do not appear to produce an appreciable antidepressant effect.'^^1 However, these neurotransmitter systems can also be influenced by different substances. Stimulant drugs, such as cocaine and amphetamines, exert their effects mainly through their effect on brain catecholamine concentrations;'"^' alcohol, tobacco and caffeine also act via mechanisms including manipulation of neurotransmitter concentrations in the CNS.
4.2.5 Caffeine

Caffeine has been shown to exert ergogenic effects in normal ambient temperature,'"^"'^'! probably related to the antagonism of adenosine receptors in the brain, resulting in increased dopamine neurotransmission. However, only one study has examined the effects of adenosine receptor antagonism in high environmental
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This Study showed that caffeine did not alter exercise performance in a preloaded time trial. The authors found increased core temperatures during exercise - which was non-attributable to metabolic heat production, as subjects did not average higher power outputs - that were probably related to the influence of caffeine on the adenosine receptor and consequently dopamine. Very recently, we performed a study (Roelands et al,, unpublished data) with caffeine manipulation in high temperature. Results were identical to the results obtained by Cheuvront et al,''^^' From these two studies it became clear that environmental conditions play an important role in the effects mediated by caffeine,
4.2.6 Summary

system. Apparently, when pharmacological manipulations are made, the anticipatory system can be modified, as was shown in both human''*'-''^'''^' and animal studies,'^''^'' 5. Conclusions Originally, fatigue was attributed solely to peripheral factors, such as muscular and cardiovascular factors. In the last few decades there has been proof that fatigue can also occur at the level of the brain. This so-called central fatigue compromises specific alterations in the functioning of the CNS and can be divided into two major aspects: (i) neuromuscular fatigue, which is the change in voluntary activation of the muscle, originating from the CNS; and (ii) actions of different neurotransmitter systems that evoke central fatigue. Studies have tried to find the mechanisms by which central fatigue takes place, using indirect manipulations with different drugs known to evoke certain influences on central neurotransmission. There is convincing evidence in animals for the existence of central fatigue. Different animal studies in normothermia were able to show that increased serotonin activity in the CNS caused the onset of fatigue, especially when combined with a decrease in dopamine,'^'*'^''' This result is not found in humans exercising in normal ambient temperature. It seems that serotonin is not the sole factor in the onset of fatigue, Dopamine has been shown to influence performance and increase core temperature when amphetamines were administered. Although the inhibition of the reuptake of dopamine increased core temperature, it did not induce any differences in performance in normothermia, Noradrenaline decreased performance and showed a small hypothermie effect. The above indicates that catecholaminergic neurotransmission will be implicated in the onset of fatigue and changes in thermal regulation in normal ambient temperature. Serotonin, dopamine and noradrenaline have been implicated in the control of thermorgulation and are thought to mediate thermoregulatory responses,'"^' especially as their neurons innervate areas of the hypothalamus, the human thermoregulatory centre, which also includes the PO/AH,
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In contrast to pharmacological manipulations in normal ambient temperature, manipulations of catecholamine levels via different reuptake inhibitors in the heat caused performance differences. Manipulation of the serotonin neurotransmitter level through reuptake inhibition did not influence performance, contradictory to the central fatigue hypothesis. Serotonin might be involved in the onset of fatigue, but in combination with other neurotransmitter systems, Dopamine has shown ergogenic effects and seems to override inhibitory signals from the CNS to stop exercising when core temperature becomes high. Core temperatures, increasing above 40C, are attained after dopamine reuptake inhibition, without any changes in the perception of effort and thermal strain. As the 'safety brake' seems to be eliminated, authors have suggested that there is a potential danger for the development of heat illness,''*-'' In contrast, noradrenaline reuptake inhibition led to slower performances and slightly lower core temperatures compared with a placebo. Taken together it appears that the catecholamines dopamine and noradrenaline have a much larger influence on fatigue, elicited via central neurotransmission, than does serotonin, indicating that the 'original' central fatigue hypothesis does not hold, especially when exercising in the heat. We have to take into account that in these trials there appears to be a complex regulatory system that integrates peripheral and central elements of fatigue into a teleoanticipatory pacing
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Increases in core and brain temperature might be important factors in the onset of fatigue,^^^' and it is known that a high ambient temperature is detrimental to exercise capacity. The combination of exercise and the manipulation of central neurotransmission in the heat may elucidate the mechanisms of fatigue. From these studies it was shown that dopamine significantly enhanced performance, coinciding with the attainment of high core temperatures and higher heart rates, without any change in thermosensation or the perception of effort. It seems that the safety mechanisms in the body are overridden due to increased dopaminergic activity. Increased brain concentration of noradrenaline strongly decreased performance in the heat and no negative effect of serotonin could be detected. Thermal regulation appears to be an important factor that will be influenced mainly by brain dopamine and noradrenaline in the PO/ AH, although the exact role of other neurotransmitter systems is not clear. It is very unlikely that one neurotransmitter system is responsible for the appearance of central fatigue. Most probably, central fatigue is caused by a complex interplay between the different neurotransmitters systems, with the most important role for the catecholamines dopamine and noradrenaline. Although work to date has given us clear observations on external behavioural changes after pharmacological interventions, the exact role of the different brain areas linked to exercise capacity and thermorgulation have yet to be elucidated.
Aci<nowiedgements
We acknowledge the valuable work from Maria Francesca Piacentini, Hiroshi Hasegawa, Phil Watson, Luk Buyse, Guy De Schutter and Frank Pauwels. We also wish to acknowledge the help from funding from the Vrije Universiteit Brssel (OZR 607, 990, 1235). The authors have no conflicts of interest that are directly relevant to the content of this review.

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formance in the heat. Am J Physiol Regul Integr Cottip Physiol 2009 Feb; 296 (2): R394-401 ~~~~~~~~~"~"~~~~~~~~~~~~^~^~~~~~~~~~~~ Correspondence: Professor Dr Romain Meeusen, Department of Human Physiology and Sports Medicine, Pleinlaan 2, B-1050 Brussels, Belgium. E-mail: rmeeusen@vub,ac,be

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