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Scand J Med Sci Sports 2010: 20 (Suppl. 3): 19–28
doi: 10.1111/j.1600-0838.2010.01205.x

& 2010 John Wiley & Sons A/S

Review

Central fatigue and neurotransmitters, can thermoregulation
be manipulated?
R. Meeusen, B. Roelands
Department of Human Physiology & Sports Medicine, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel,
Brussels, Belgium

Corresponding author: Prof. Dr. Romain Meeusen Department of Human Physiology and Sports Medicine, Pleinlaan 2,
B-1050 Brussels, Belgium, Tel:132 2 6292222, Fax:132 2 6292876, E-mail: rmeeusen@vub.ac.be
Accepted for publication 22 July 2010

Fatigue is a complex phenomenon that can be evoked by
peripheral and central factors. Although it is obvious that
fatigue has peripheral causes such as glycogen depletion and
cardiovascular strain, recent literature also focuses on the
central origin of fatigue. It is clear that different brain
neurotransmitters – such as serotonin, dopamine and noradrenaline – are implicated in the occurrence of fatigue, but
manipulation of these neurotransmitters produced no conclusive results on performance in normal ambient temperature. Exercise in the heat not only adds an extra challenge to
the cardiorespiratory system, but also to the brain. This
provides a useful tool to investigate the association between

exercise-induced hyperthermia and central fatigue. This review focuses on the effects of pharmacological manipulations
on performance and thermoregulation in different ambient
temperatures. Dopaminergic reuptake inhibition appears to
counteract hyperthermia-induced fatigue in 30 1C, while
noradrenergic neurotransmission shows negative effects on
performance in both normal and high temperature, and
serotonergic manipulations did not lead to significant changes
in performance. It is, however, unlikely that one neurotransmitter system is responsible for the delay or onset of fatigue.
Further research is required to determine the exact mechanisms of fatigue in different environmental conditions.

The causes of fatigue are believed to be of peripheral
and central origin, therefore, fatigue should be acknowledged as a complex phenomenon influenced by
several factors. Fatigue during prolonged exercise
has traditionally been attributed to the occurrence of
a ‘‘metabolic end point,’’ where muscle glycogen
concentrations are depleted (Bergstrom et al.,
1967). Also, cardiovascular (Rowell et al., 1966;
Gonza´lez-Alonso & Calbet, 2003), metabolic and
thermoregulatory strain (Hargreaves & Febbraio,
1998; Gonzalez-Alonso et al., 1999b) are possible
peripheral candidates for the occurrence of fatigue
during prolonged exercise.
Romanowski and Grabiec (1974) linked the
changes in brain neurotransmission – in particular
serotonin (5-HT) – to a possible inhibition of brain
oxidoreductive processes, while others (Heyes et al.,
1985; Davis and Bailey, 1997) highlighted the role of
dopamine (DA) and noradrenaline (NA) related to
changes in performance. In 1987, Newsholme and his
co-workers hypothesized that fatigue was caused by an
increase in brain 5-HT concentration, which induced
negative effects on arousal, lethargy, sleepiness and
mood. Through this mechanism the perception of
effort and fatigue could be altered (Newsholme et al.,
1987). The Central Fatigue hypothesis potentiated

new opportunities for research. Many studies challenged the ‘‘central fatigue’’ hypothesis. Davis and
Bailey (1997) showed that not only increases in 5HT, but an interaction between 5-HT/DA would
influence central nervous system fatigue. A low ratio
favors improved performance and a high ratio decreases motivation and augments lethargy, consequently decreasing performance (Davis & Bailey,
1997).
Both pharmacological and nutritional manipulations have been applied, aiming at influencing one or
more brain neurotransmitters (predominantly 5-HT,
DA and NA), to delay or accelerate the onset of
fatigue during prolonged exercise (1–3 h). Most studies were performed in normal ambient temperature
(see Table 1; for review Meeusen et al., 2006b). But,
as 5-HT, DA and NA have all been implicated in the
control of thermoregulation and are thought to
mediate thermoregulatory responses (Bridge et al.,
2003), it can be expected that a shift in the concentrations of these neurotransmitters contributes to
changes in thermal regulation and fatigue resistance.
For that reason, heat stress in combination with
the manipulation of different neurotransmitter
systems on fatigue in normal ambient temperature,
was explored in different studies. Although recently

19

20
Buspirone

Paroxetine
Fluoxetine
Acute fluoxetine
Chronic fluoxetine
Reboxetine
Venlafaxine
Bupropion
Modafinil
Bupropion
Ritalin
Reboxetine
Citalopram

Men, n 5 13

Men, n 5 7 (trained)

Men, n 5 10

Men, n 5 8 (trained)

Men, n 5 11
Men, n 5 12
Men, n 5 7 (trained)

Men, n 5 7 (trained)

Men, n 5 8 (trained)

Men, n 5 15

Men, n 5 8 (trained)

Men, n 5 8 (trained)

Men, n 5 9 (trained)

Men, n 5 9 (trained

Marvin et al. (1997)

Meeusen et al. (1997)

Struder et al. (1998)

Meeusen et al. (2001)

Parise et al. (2001)

Piacentini et al. (2002a)

Piacentini et al. (2002b)

Piacentini et al. (2004)

Jacobs and Bell (2004)

Watson et al. (2005)

Roelands et al (2008b)

Roelands et al (2008a)

Roelands et al (2009a)

5-HT1Aagonist

5-HT2Cantagonist

Cycling (60 min at 55%
Wattmax)130-min TT
Cycling (60 min at 55%
Wattmax)130-min TT

Cycling at 85% VO2max to
exhaustion
Cycling (60-min at 55%
Wattmax)130-min TT
Cycling (60 min at 55%
Wattmax)130-min TT

90-min TT

90-min TT

Wingate and 80% VO2max to fatigue
Wingate and 90% VO2max to fatigue
90-min TT

Cycling at 2mmol/l blood lactate to
exhaustion
90-min TT

Cycling at 30% VO2max to
exhaustion
Cycling at 70% VO2max to
exhaustion incremental test to
exhaustion
Treadmill running at 70% VO2max to
exhaustion
Cycling at 80% VO2max to
exhaustion
Cycling at 65% VO2max to
exhaustion
Cycling at 65% VO2max to
exhaustion

Exercise protocol

181C

181C

181C

181C

181C

181C

181C

181C

181C

181C

Ambient
temperature

TT performance !, Tre and HR",
Tsk, RPE and thermal strees !
TT performance !, Tre and
HR !, Tsk, RPE and thermal
stress !
TT performance#, Tre and HR",
Tsk, RPE and thermal stress !
TT performance !, Tre and
HR !, Tsk, RPE and thermal
stress !

TT performance !
HR, RPE, FFA, LA, Glucose and
NH3 !
No difference in either test
No difference in either test
TT performance !
HR, RPE and LA !
TT performance !
HRand LA !
TT performance !
HR, RPE & LA !
TTE", RPE#

HR, FFA, LA, NH3, NA, A and DA"
during exercise L-DOPA; HR, LA,
DA" at rest compared with placebo
TTE#
TTE#

Exercise performance !

TTE#

TTE#
Total work ! , VO2max, plasma
NH3
TTE !

TIE#

Results

DA, dopamine; FFA, free fatty acid; HR, heart rate; 5-HT, 5-hydroxtryptamine; LA, lactate; NA, nordrenaline; NH3, ammonia; RPE, ratings of perceived exertion; Tre, rectal temperature; Tsk, skin temperature; TT, time trial;
TTE, run time to exhaustion; ", significant increase; #, significant decrease; !, no difference.

5-HT reuptake inhibitor

NA reuptake inhibitor

DA reuptake inhibitor

Psychostimulant drug a1adrenergic agonist
DA/NA reuptake inhibitor

DA/NA reuptake inhibitor

5-HT/NA reuptake inhibitor

5-HT reuptake inhibitor
5-HT reuptake inhibitor
NA reuptake inhibitor

5-HT reuptake inhibitor

5-HT reuptake inhibitor

5-HT2A/2C antagonist

Pizotifen

Men, n 5 8

Pannier et al. (1995)

5-HT reuptake inhibitor

Ritanserin

Fluoxetine

Men, n 5 6

Davis et al. (1993)

5-HT reuptake inhibitor

DA precursor

Paroxetine

Men, n 5 7

Wilson and Maughan (1992)

Details

L-DOPA

Manipulation

Subjects

References

Table 1. Pharmacological manipulations of central neurotransmission in humans in normal ambient temperature

Meeusen & Roelands

Central fatigue
also more focus is put on the perception of fatigue as
a model for central fatigue (St Clair Gibson et al.,
2003), other mechanisms can also be responsible for
premature fatigue during prolonged exercise such as
disturbed cerebral metabolism as well as changes in
neurohumoral or neurotransmitter responses during
exercise (Nybo & Secher, 2004). The processes that
lead to decrements in performance can occur at every
level of the brain-muscle pathway (Taylor et al.,
2006). We direct the readers towards the work of St
Clair Gibson et al. (2006), Marino (2004) and others
on the perception of effort and possible integration of
central and peripheral signals during exercise.
The purpose of this review is to briefly describe the
possible role of neurotransmitters during prolonged
exercise in thermoneutral conditions. This is followed
by an overview of the effects of warm environmental
temperature on performance, and studies that used
exercise with superimposed heat stress as a ‘‘fatigue
model’’ for studying the potential involvement of
different neurotransmitter systems.
Brain manipulations in normal ambient temperature
It is clear that exercise influences brain neurotransmission (Meeusen & De Meirleir 1995), increasing
the concentration of different neurotransmitters
(Chaouloff et al., 1986). Bailey et al. (1993) extended
this observation by demonstrating the importance
of increased brain DA synthesis and metabolism
during exercise. They found that fatigue in the rat
is associated with high levels of 5-HT and a reduction
of dopamine in the brain stem and midbrain.
Furthermore, when brain DA synthesis and metabolism is maintained, fatigue is delayed (Bailey et al.,
1993).
Manipulation of 5-HT in humans did not lead to
such conclusive results. Some studies (Wilson &
Maughan, 1992; Davis et al., 1993; Struder et al.,
1998) did detect performance decrements after administration of paroxetine and fluoxetine (5-HT reuptake
inhibitors). Most studies, however, were not able to
confirm these findings (Pannier et al., 1995; Meeusen
et al., 1997; Meeusen et al., 2001; Parise et al., 2001;
Roelands et al., 2009a). Struder and Weicker (2001)
suggested that the reduction of performance capacity
found after acute administration of 5-HT reuptake
inhibitors might be due to a diminished regulatory
capacity of the 5-HT system as multifunctional generator providing the cerebral adaptability of the
neural network to cope with vital central requirements, rather than an increase in 5-HT activity.
Furthermore, Struder and Weicker (2001) state that
well-adapted athletes might be able to compensate
excessive increases of brain 5-HT formation.
Because of the complexity of brain functioning and
the contradictory results from the studies that tried

to manipulate only serotonergic activity, it appears
unlikely that a single neurotransmitter system is
responsible for the central component of fatigue. In
fact, alterations in serotonin, catecholamines, amino
acid neurotransmitters (glutamate, GABA) and acetylcholine have all been implicated as possible mediators of central fatigue during exercise (Meeusen &
De Meirleir, 1995). These neurotransmitters are
known to play a role in arousal, mood, motivation,
vigilance, anxiety and reward mechanisms, and could
therefore, if adversely affected, impair performance.
DA neurotransmission has been shown to improve
performance when amphetamines were administered
(Borg et al., 1972). The inhibition of the reuptake of
DA also increases core temperature at the end of
exercise, but no effect on performance was found in
normothermia (Watson et al., 2005; Roelands et al.,
2008b), while the administration of a NA reuptake
inhibitor decreases performance and showed a small
hypothermic effect in normal ambient temperature
(Piacentini et al., 2002a; Roelands et al., 2008a). The
above indicates that catecholaminergic neurotransmission will be implicated in the onset of fatigue and
changes in thermal regulation in normal ambient
temperature. An overview of all studies performed in
normal ambient temperature can be found in Table 1.

Brain manipulations in high ambient temperature
Exercise performance in the heat

When exercising in uncompensable heat stress, heat
production exceeds the capacity for heat release to
the environment, thereby elevating skin and core
temperature (Cheung & McLellan, 1998). Several
studies showed that exercise capacity is better in
low ambient temperatures (cycling at 70% VO2max
until exhaustion; Galloway & Maughan. 1997; Parkin et al., 1999), with a progressive fall in time until
exhaustion as ambient temperature increases. This
unfavorable effect of a high environmental temperature on performance can not only be associated with
muscular and peripheral factors, as these are not
altered to such an extent that it would explain the
diminished endurance capacity during prolonged
exercise in the heat (Nybo & Secher, 2004). In some
cases, muscle glycogen stores are far from depleted,
muscle and blood lactate concentrations are not
higher than compared with exhausting exercise in
normal ambient temperature, and potassium release
does not explain the hyperthermia-induced fatigue
either (Nielsen et al., 1990, 1993, 1997; GonzalezAlonso et al., 1999a). Both Bru¨ck and Olschewski
(1987) and Nielsen et al. (1993, 1997) suggested that
during prolonged MVCs, performance in the heat is
primarily regulated by a diminished drive from the
central nervous system.

21

Meeusen & Roelands
In recent literature two plausible mechanisms have
been put forward for how hyperthermia induced
fatigue might limit performance (Cheung, 2007). It
is hypothesized that the approach or attainment of a
high core and brain temperature, before the point of
collapse is reached, is a signal for the appearance of
exhaustion. Morrison et al. (2004) showed a progressive central impairment with increasing core temperature after passive heating. Furthermore, this
model was developed based upon observations of
consistent muscle and core temperatures at the point
of voluntary termination of exercise despite starting
at different core temperatures and rates of heat
storage (MacDougall et al., 1974; Nielsen et al.,
1993; Gonzalez-Alonso et al., 1999b; Walters et al.,
2000). In this way the body protects itself against
potential tissular damage. It thus seems that during
exercise with severe heat stress, a high body temperature may directly or indirectly influence endurance
performance. Literature has suggested the existence
of a ‘‘critical’’ core temperature (Nielsen et al., 1993).
This comes from observations in which subjects
terminate exercise at the same core temperature,
despite having started at different core temperatures
and having performed different exercise times (Fuller
et al., 1998; Gonzalez-Alonso et al., 1999b). Recently
however the concept of a ‘‘critical’’ core temperature
has been challenged. During sports competition welltrained athletes may attain core temperatures well
above 40 1C (Byrne et al., 2006; Ng et al., 2008; Ely et
al, 2009). Ely et al. (2009) showed that the attainment
of a critical core temperature (40 1C) did not slow
running velocity when skin temperatures remained
modest during an 8 km training time trial in environmental conditions favorable for heat exchange. Finally, pharmacological manipulations increasing DA
neurotransmission have also shown to push subjects
above 40 1C (Watson et al., 2005; Roelands et al.,
2008b). From this point of view the ‘‘critical’’ core
temperature should not be seen as an all or nothing
phenomenon, but rather as a continuum with a
complex interplay from multiple physiological systems (Ely et al., 2009).
The second mechanism states that complex feed
forward and feedback mechanisms regulate fatigue.
Recently it has been suggested that exercise performance in the heat is governed through an anticipatory response that reduces skeletal muscle
recruitment, thus limiting the rate of heat production
(Marino et al., 2004; Tucker et al., 2004). A feedforward regulation of power output may insure that
the rate of body heat accumulation is restricted to
prevent the development of heat illness. However, a
recent article presented by Shephard (2009) argues
against the existence of a so-called ‘‘central governor.’’ Until now, there is a lack of convincing
scientific evidence for this hypothesis and some

22

findings, such as the consistent oxygen plateau in
young adults, strongly argue against the limiting role
of the ‘‘central governor’’ (for a review, see Shephard, 2009).
Both mechanisms are probably linked to each
other and can be influenced through manipulation
of different brain neurotransmitters (see Cheung,
2007 for a review). The brain monoamines 5-HT,
DA and NA innervate different areas of the hypothalamus, among which also the preoptic and anterior
hypothalamus (PO/AH). The PO/AH is thought to
be the primary locus for body temperature regulation
(Boulant & Dean, 1986) due to the fact that the PO/
AH contains both warm-sensitive and cold-sensitive
neurons. These respond to small changes in temperature (Boulant, 1974, Nakayama et al., 1961). This
brain area integrates thermal information from central and peripheral thermoreceptors, and initiates
appropriate heat loss and heat production responses.
It is well known that NA and DA in the hypothalamic regions play essential roles in thermoregulation. For example, local application of NA into the
rat PO/AH causes an increase in body temperature
(Clark & Lipton, 1986), and NA inhibits the activities of warm-sensitive neurons in the PO/AH (Watanabe et al., 1986). These findings suggest that NA is
involved in heat production mechanisms. On the
other hand, Quan et al. (1991, 1992) have shown
that NA microdialyzed into the PO of conscious
guinea pigs evokes a fall in core temperature that is
mediated by a reduction in metabolic rate. It has also
been reported that DA excites the firing rate of
warm-sensitive neurons and inhibits cold-sensitive
neurons in tissue slices of the PO/AH (Scott &
Boulant, 1984). In addition, microinjections of apomorphine (a DA agonist) into the hypothalamus of
the rat produced a DA mediated decrease in temperature (Brown et al., 1982). Moreover, DA release
in the PO/AH is enhanced during treadmill exercise
(Hasegawa et al., 2005) and DA induces an increase
in body temperature in rats (Myers & Yaksh, 1968).
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 (Roelands & Meeusen, 2010).
Table 2 presents an overview of all studies manipulating brain neurotransmission in high ambient
temperature.
The role of dopamine
Early studies applying amphetamines, well-known
DA releasers, showed significant increases in performance in both animal (Gerald, 1978; Heyes et al.,
1985) and human (Wyndham et al., 1971; Borg,
1972) studies.

Central fatigue
Table 2. Pharmacological manipulations of central neurotransmission in humans in high ambient temperature

References

Subjects

Manipulation Details

Bridge et al.
(2003)

Men, n 5 12

Buspirone

Exercise protocol

5-HT1A agonist Cycling at 73%
& D2 antagonist Vo2max to exhaustion

Ambient
Results
temperature
351C

Positive relationship
between TTE and
non-5-HT component (DA)

Buspirone1pindolol

Strachan et al.
(2004)
Strachan et al.
(2005)
Watson et al.
(2005)

Negative relationship
between rate of Tre
increase and non-5-HT
component
Men, n 5 8

Paroxetine

5-HT reuptake
inhibitor

Cycling at 60%
VO2max to exhaustion

321C

TTE !

Men, n 5 6 (trained)

Pizotifen

5-HT2C
antagonist

40 km TT

35.51C

Tre"
TT performance !

Women, n 5 1
(trained)
Men, n 5 8 (trained)

Bupropion

DA/NA reuptake
inhibitor

Cycling (60 min 55%
Wattmax)130-min TT

301C

Roelands et al.
(2009b)

Men, n 5 8 (trained)

Chronic
Bupropion

DA/NA reuptake
inhibitor

Cycling (60 min 55%
Wattmax)130-min TT

301C

Roelands et al.
(2008b)

Men, n 5 9 (trained)

Ritalin

DA reuptake
inhibitor

Cycling (60 min 55%
Wattmax)130-min TT

301C

Roelands et al.
(2008a)

Men, n 5 9 (trained)

Reboxetine

NA reuptake
inhibitor

Cycling (60 min 55%
Wattmax)130-min TT

301C

Roelands et al.
(2009a)

Men, n 5 11 (trained)

Citaolpram

5-HT reuptake
inhibitor

Cycling (60 min 55%
Wattmax)130-min TT

301C

Tre" at rest compared
with placebo
TT performance", Tre and
HR", Tsk, RPE and
thermal stress !
TT performance !, Tre"
and HR, Tsk, RPE and
thermal stress !
TT performance", Tre and
HR", Tsk, RPE and
thermal stress !
TT performance#, Tre#,
HR", thermal stress#,
Tsk, RPE !
TT performance !, Tre
and HR#, Tsk, RPE and
thermal stress !

Tsk, skin temperature; TT, time trial; TTE, run time to exhaustions; DA, dopamine; HR, heart rate; 5-HT, 5-hydroxytryptamine; NA, noradrenaline; RPE,
ratings of perceived exertion; Tre, rectal temperature; ", significant increase; #, significant decrease; !, no difference.

In the past, different studies failed to show a
performance enhancement through manipulation of
the catecholaminergic neurotransmission in normal
ambient temperature (Meeusen et al., 1997; Piacentini et al., 2002a, b, 2004). Watson et al. (2005)
investigated the effects of a dual DA/NA reuptake
inhibitor (bupropion) during prolonged exercise in
18 and 30 1C. A time trial to measure performance
was proceeded by a 60-min fixed intensity exercise to
ensure the fatiguing characteristics of the experimental trial. In normal ambient temperature, no difference was found between the placebo and bupropion
trial. At 30 1C, however, subjects cycled over 3 min
(9%) faster when bupropion was administered. In a
follow-up study, we applied the same protocol and
administered methylphenidate to our subjects (Roelands et al., 2008b). Again, in normal ambient
temperature, no difference in performance was present between the placebo and drug trial. In the heat,
however, the time taken to complete the predetermined amount of work was over 7 min or 16%
shorter after administration of methylphenidate
compared with the placebo. The discrepancy between
the effects of these drugs in normal and high ambient
temperature can be explained by a DA-mediated

increase in motivation to continue exercise (Foley
& Fleshner, 2008). The increased DA concentrations
after DA reuptake inhibition will counteract the
hyperthermia-induced decrease in motivation and
drive (Del Arco & Mora, 2009), consequently allowing subjects to push harder and improve exercise
performance. This ergogenic effect found when DA
concentration is increased is presumably mediated
through stimulation of the ventral tegmental area.
Burgess et al. (1991) reported that intracranial selfstimulation of the ventral tegmental area was more
capable to motivate treadmill running in rats compared to the electric shock motivation.
Besides the central ergogenic effects of the manipulation of DA, also final core temperature increased
much higher in comparison with the placebo situation in the heat. In the bupropion trial in the heat,
seven out of nine subjects showed an increase in core
temperature at the end of exercise to or above
40.0 1C (Watson et al., 2005). After methylphenidate
administration in the heat, the average final core
temperature increased to 40.0 1C at the end of
exercise (Roelands et al., 2008b). The combination
of the brain manipulation of DA, high ambient
temperature, a strong ergogenic effect and the attain-

23

Meeusen & Roelands
ment of very high core temperatures at the end of
exercise confirms the suggestion made by Bridge
et al. (2003) that perturbing DA can alter exercise
capacity in the heat.
Despite reaching high core temperatures at the end
of exercise in both the bupropion (Watson et al.,
2005) and the methylphenidate (Roelands et al.
2008b) trials, there were no changes in the thermal
sensation scores. Although the subjects’ heart rate
and power output were higher, ratings of perceived
exertion were identical when compared with placebo.
Thus, it appears that mechanisms existing in the
body to prevent harmful effects are dampened or
overridden when the reuptake of DA is inhibited
through pharmacological agents.
This was emphasized by Hasegawa et al. (2005)
who examined the effects of an acute dose of bupropion on brain, core and tail skin temperature in freely
moving rats. The authors measured the extracellular
neurotransmitter concentrations in the PO/AH. As
expected, bupropion significantly increased extracellular DA and NA concentrations without exerting an
effect on 5-HT. The most important finding in this
study was that bupropion altered thermoregulation
in the rats. Tail temperature, an indicator of heat
dissipation, was significantly lower after bupropion
injection, while both brain and core temperature
were significantly elevated.
A follow-up study (Hasegawa et al., 2008) injected
rats with bupropion before the start of a run until
exhaustion trial in the heat (30 1C). The main finding
of this study was that an acute injection of bupropion
improved exercise performance and induced an increase in both core and brain temperature during
exercise in a warm environment compared with the
placebo trial in the heat. These changes in temperature were accompanied by an increase in the extracellular concentrations of DA and NA in the PO/AH
in exercising rats. Again, rat tail temperature was
lower in the bupropion trial indicating a negative
effect on heat dissipation mechanisms. These results
not only confirm our human data, but also showed
that the acute injection of bupropion acts on the
brain by influencing brain temperature and specific
neurotransmitters in the thermoregulatory centre
during exercise in the heat. The results also indicate
that the so-called ‘‘critical’’ core temperature can be
bypassed when animals are running in the heat in the
presence of high concentrations of catecholamines
(Hasegawa et al., 2008).
Bupropions’ potency as an inhibitor of NA is onehalf of that of DA (Ascher et al., 1995) when
administered acutely. No data are, however, available on this relationship when this drug is chronically
administered. Therefore in a recent study we applied
bupropion for 10 days (Roelands et al., 2009b).
Subjects performed a 30-min time trial after a 60-

24

min fixed intensity exercise in the heat. No effect on
time trial performance was found, while final core
temperatures were still elevated above the level of the
placebo trial. Mean maximal core temperatures at
the end of exercise increased, however, only to
39.6 1C, which is lower than in the acute bupropion
trial. The reason for the diminished action after
chronic bupropion administration will probably be
linked to a change in central neurotransmitter homeostasis (Roelands et al., 2009b). After approximately
7 days, bupropion and its metabolites reach steadystate levels (Jefferson et al., 2005). Peak plasma levels
of chronic administration are similar compared to
levels reached after an acute dosing. The levels of
hydroxybupropion, the major metabolite of bupropion, that acts on the NA transporter, are four times
higher at steady state compared with acute administration (Rusyniak et al., 2007). Logically, the concentration of hydroxybupropion gains significance as
the ratio bupropion/hydroxybupropion is firmly decreased, consequently increasing the concentration of
NA (Roelands et al., 2009b).
The role of noradrenaline
A recent study (Roelands et al., 2008a) shows that an
increase in the concentration of NA might be unfavorable for exercise performance. Administration
of reboxetine, a NA reuptake inhibitor, previously
showed a trend toward a decrease in performance in
normal ambient temperature (Piacentini et al.,
2002a). The same drug was detrimental for exercise
performance in the heat: subjects cycled 20% longer
to complete the same amount of work in comparison
with the placebo trial. Subjects’ thermal sensation
was disturbed as they felt colder before and during
exercise and also core temperatures throughout exercise tended to be lower. This confirms previous
results from animal studies that found hypothermic
effects after NA manipulation (Gisolfi & Cristman,
1980; Myers et al., 1987; Quan et al., 1991, 1992).
Interestingly, compared with the placebo situation,
heart rates increased significantly after NA reuptake
inhibition at rest and during exercise, a finding that
can be explained by a combination of both central
and peripheral factors. Augmented NA concentrations are able to increase sympathomimetic activity
(Szabadi et al., 1998), but possibly it also augments
central NA inhibition in the parasympathetic nuclei,
causing lower cardiac parasympathetic tone and an
increase in heart rate (Schu¨le et al., 2004).
The negative effect on performance found after
NA reuptake inhibition is in a way unexpected
because NA mechanisms are thought to be involved
in the control of level of arousal, consciousness, and
reward mechanisms in the brain (Montgomery, 1997;
Meeusen et al., 2006a, b). Through this mechanism it

Central fatigue
could be suggested that NA plays a role in the
regulation of performance. On the other hand, it is
well established that NA neurons modulate the 5-HT
system via excitatory a1-adrenoceptors. In the brain
stem, dorsal raphe 5-HT neurons receive ascending
NA neuron afferents originating from the locus
coeruleus (Szabo & Blier, 2001). 5-HT has been
implicated in central fatigue (Meeusen et al.,
2006b), and there is pharmacological evidence (Wilson & Maughan, 1992; Struder et al., 1998) from
both animal and human studies that is consistent
with the result found after NA reuptake inhibition.
The role of serotonin
As stated before, 5-HT was put forward as the
important neurotransmitter at the origin of central
fatigue. However, when looking closer to literature
that reported on the effects of the manipulation of 5HT in the brain during exercise in the heat, results do
not support this theory. Strachan et al. (2004) examined the effects of the 5-HT reuptake inhibitor
paroxetine in 32 1C in a time to exhaustion trial. No
evidence for detrimental effects of 5-HT on exercise
capacity was detected. Final core temperature was
slightly higher after administration of paroxetine,
suggesting that it acts as a postsynaptic 5-HT agonist
(Lin et al., 1998). This increase in core temperature
might have been too small to evoke any negative
effects on performance (Strachan et al., 2004).
In a follow-up study (Strachan et al., 2005),
pizotifen, a selective 5-HT2C receptor antagonist;
was administered. The goal was to examine whether
blockade of 5-HT2C receptors would induce changes
in performance and thermoregulatory parameters.
Subjects had to perform a 40 km time trial in the
heat. Rectal temperature was significantly increased
by pizotifen before (P 5 0.03) and during (Po0.05)
exercise, thereby confirming that the 5-HT2 receptor
family has a role in thermoregulation. However, the
higher rectal temperatures did not induce any change
in performance (Strachan et al., 2005).
In our laboratory, we recently studied the effects of
acute citalopram (5-HT reuptake inhibitor) administration. No significant influence on performance on a
preloaded time trial in the heat was detected (Roelands et al., 2009a). There was a tendency for core
temperatures to be lower during exercise, while
during recovery this difference was significant. No
changes in thermal stress scores and RPE were
reported. This contradicts the studies by Strachan
et al. (2004, 2005), who found slight increases in core
temperature after manipulation of the 5-HT neurotransmission. Several animal studies have examined
the relationship between 5-HT and thermoregulation. Local application of 5-HT into the PO/AH was
reported to alter the activities of thermosensitive

neurons (Watanabe et al., 1986). Feldberg and Myers
(1963) reported that microinjection of 5-HT into the
PO/AH induced an increase in body core temperature. Recently, Ishiwata et al. (2004) showed that the
perfusion of a 5-HT re-uptake inhibitor or 5-HT1A
agonist, into the PO/AH did not affect core temperature. This is despite the fact that extracellular 5-HT
in the PO/AH was increased or decreased in freely
moving rats (Ishiwata et al., 2004). The authors
suggested that hypothalamic 5-HT may not mediate
acute changes in thermoregulation.
Taken together, the results from both human and
animal studies once more show how difficult it is to
interpret the effects of different drugs, even when
they act on the same neurotransmitter. The results
indicate a role for several DA and 5-HT transmitter
receptors in motor control and ‘‘central fatigue.’’
However, any possible role of 5-HT, DA (and other
transmitters) in motor function should be perceived
as a continuum (Davis & Bailey, 1994). This continuum is not only important at the brain level, but
has its own importance in the interaction between
central neurotransmission and the peripheral processes during exercise, including the neuroendocrine
system, especially the activity of the hypothalamic–
pituitary–adrenal axis. Neurotransmitter systems not
only influence each other, but they also are intimately
linked. For 5-HT it appears that drugs acting on the
5-HT2 receptor family are capable of influencing core
temperature (Strachan et al., 2005). Knowing that
there are several families of 5-HT receptor subtypes
(Zifa & Fillion, 1992), each with different functions
and interactions, and that neurotransmitters constantly interact, we need to consider the possibility
that as we progress in science, future studies will
identify new possible mechanisms.
Many questions remain to be answered regarding
the hypothesized mechanisms of action, and the
physiological and psychological effects of endurance
exercise performance, training, and fatigue. What
remains to be seen is how individual elements of
the several neurotransmitters and neuromodulators
contribute to this scheme: how modulation of preand postsynaptic receptors, coupled with rapid or
delayed changes in transmitter synthesis and release,
accounts for the behavioral and performance impact
on fatigue.
Perspective
Pharmacological manipulations during prolonged
exercise in both normal and high ambient temperature will result in different effects depending on the
environmental temperature and on the neurotransmitter systems that have been manipulated (see
Fig. 1). In the heat, DA has shown clear ergogenic
effects and seems to override inhibitory signals from

25

Meeusen & Roelands

Performance difference (%)

25

18°C

30°C

20
15
10
5
0
–5
–10
–15
–20

Fig. 1. Effects of pharmacological manipulations performed
in both normal and high ambient temperature on performance (in %). CITAL, citalopram (Roelands et al., 2009a);
REBOX, reboxetine (Roelands et al., 2008a); MPH, methylphenidate (Roelands et al., 2008b); AC BUP, acute bupropion (Watson et al., 2005); CHR BUP, chronic bupropion
(Roelands et al., 2009b).

the central nervous system to stop exercising when
core temperature becomes high. NA reuptake inhibition induced negative effects on performance during
prolonged exercise and lower core temperatures during and at the end of exercise compared with the

placebo situation in both normal and high ambient
temperature. Taken together, it appears that the
catecholamines DA and NA have a large influence
on performance during prolonged exercise, certainly
when this exercise is carried out in high ambient
temperature. Although recent literature provides a
ground for possible mechanisms of fatigue, specifically in the heat, there are still a number of aspects
that need to be explored before any definitive conclusions can be made. Finally, we do not have to look
at the present research data as being contradictory or
inconsistent, it probably just means that we are only
at the beginning of ‘‘the age of the brain.’’
Key words: central fatigue, pharmacological manipulation, exercise performance, heat.

Acknowledgements
We wish to acknowledge funding from the Vrije Universiteit
Brussel (OZR 607, 990, 1235).
Conflicts of interest: BR is a postdoctoral fellow of the
Fund for Scientific Research Flanders (FWO). RM has no
potential conflicts of interest.

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