Brazilian Journal of Medical and Biological Research (2017) 50(12): e6432, http://dx.doi.org/10.

1590/1414-431X20176432
ISSN 1414-431X Review 1/13

Physical exercise-induced fatigue: the role of

serotonergic and dopaminergic systems
L.M.S. Cordeiro1, P.C.R. Rabelo1, M.M. Moraes1, F. Teixeira-Coelho1,2, C.C. Coimbra3,
S.P. Wanner1 and D.D. Soares1
1
Laboratório de Fisiologia do Exercício, Escola de Educac¸ão Física, Fisioterapia e Terapia Ocupacional,
Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
2
Centro de Formac¸ão de Professores, Universidade Federal do Recôncavo da Bahia, Amargosa, BA, Brasil
3
Laboratório de Endocrinologia e Metabolismo, Instituto de Ciências Biológicas,
Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil

Abstract

Brain serotonin and dopamine are neurotransmitters related to fatigue, a feeling that leads to reduced intensity or interruption
of physical exercises, thereby regulating performance. The present review aims to present advances on the understanding
of fatigue, which has recently been proposed as a defense mechanism instead of a ‘‘physiological failure’’ in the context of
prolonged (aerobic) exercises. We also present recent advances on the association between serotonin, dopamine and fatigue.
Experiments with rodents, which allow direct manipulation of brain serotonin and dopamine during exercise, clearly indicate that
increased serotoninergic activity reduces performance, while increased dopaminergic activity is associated with increased
performance. Nevertheless, experiments with humans, particularly those involving nutritional supplementation or pharmaco-
logical manipulations, have yielded conflicting results on the relationship between serotonin, dopamine and fatigue. The only
clear and reproducible effect observed in humans is increased performance in hot environments after treatment with inhibitors of
dopamine reuptake. Because the serotonergic and dopaminergic systems interact with each other, the serotonin-to-dopamine
ratio seems to be more relevant for determining fatigue than analyzing or manipulating only one of the two transmitters. Finally,
physical training protocols induce neuroplasticity, thus modulating the action of these neurotransmitters in order to improve
physical performance.

Key words: Brain; Lethargy; Monoamines; Performance; Physical activity; Reward

Introduction

Fatigue is a feeling commonly experienced in our daily this review. In general, the moment at which exercise
lives, for example, during periods of vigorous and/or ceases is usually termed as point of exhaustion in human
prolonged physical activity. In the sporting context, fatigue studies. However, the two terms may be related to different
is crucial to the performance of athletes in virtually all processes with distinct physiological characteristics. The
competitive events, although the determinant factors (either feeling of fatigue appears to occur before any damage to
physiological or psychological) for fatigue are specific to the body systems, and it is common to see the term ‘volitional
individual events. The present review will focus on fatigue fatigue’, indicating that subjects decided to stop exercis-
during prolonged (aerobic) exercise, thus characterizing ing. Exhaustion can be defined as extreme fatigue, a state
exertion in long-distance sports athletes, including runners, in which an individual may exceed his/her physiological
cyclists and swimmers. In these conditions, the determinant limits and then experience a ‘‘catastrophic’’ failure of home-
factors for fatigue will depend on several aspects, such as ostasis (2). In this context, the increase of core body tem-
exercise intensity and duration, environmental conditions, perature would be less in fatigued compared to exhausted
nutrition and the fitness level of the individual. For instance, individuals. Of note, severe hyperthermia induces some
regulation of body temperature plays an important role impairments, such as changes in behavior, confusion, loss
on fatigue during a prolonged exercise (B60 min) at 60% of of coordination and awareness (3), and may favor the
the maximal aerobic capacity in hot weather (1). occurrence of heat-related disorders (4). In experiments
Fatigue and exhaustion are commonly used as synon- with rats, fatigue is usually defined as the moment when the
ymous in the literature, including some studies cited in animals cannot keep the pace on a treadmill during a

Correspondence: D.D. Soares: <danusa56@gmail.com>

Received April 2, 2017 | Accepted August 25, 2017

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Serotonin, dopamine and fatigue during physical exercise 2/13

predetermined time (5). In contrast, exhaustion is confirmed nitric oxide (20). However, considering the emphasis
by the observation that exhausted rats lose their righting given to the involvement of 5-HT and DA in the develop-
reflex (i.e., the ability to right themselves when placed on ment of fatigue in studies with humans or laboratory
their backs) (5). rodents, this review will focus on the role of these two
The psycho-physiological process that triggers the neurotransmitters.
feeling of fatigue is complex and may result from peripheral
and central factors. Peripheral fatigue is defined as the loss Serotonin
of force caused by processes occurring at or distal to the
neuromuscular junction (6). In a simpler way, peripheral Serotonin (5-hydroxytryptamine; 5-HT) is a neuro-
fatigue can be thought of as fatigue within the muscle itself. transmitter synthesized from the amino acid tryptophan
Some relevant peripheral factors are specific impairments (TRP), which is transported through the blood-brain barrier
in neuromuscular transmission and impulse propagation, by a specific carrier and is then hydroxylated by the action
substrate depletion, reduction in muscle pH, dysfunction of tryptophan hydroxylase; this hydroxylation is the rate
within the sarcoplasmic reticulum involving calcium release limiting step in the biosynthesis of 5-HT. Increased plasma
and uptake, which together impair the ability of muscle levels of free TRP favor increases TRP concentrations in
fibers to generate power (7). the central nervous system (CNS), and thus any condition
In the past, fatigue was considered a consequence of that increases this amino acid in the plasma will induce
the failure of contractile processes in muscle, mainly increased concentrations in the CNS and hence the
caused by accumulation of H+ ions. However, since the central biosynthesis of 5-HT (21).
early 2000s, fatigue has been understood as a mechan- The bodies of serotonergic neurons are located in the
ism that aims to maintain the physiological integrity of CNS structures called the raphe nuclei. These nuclei are
the body (8). Signals arising from several systems are divided into caudal raphe, with descending projections to
integrated in the brain during exercise in order to stop the spinal column, and rostral and medial raphe, which
physical exertion or reduce its intensity, as a safety mechan- send ascending projections to various brain regions, such
ism to prevent the limit of physiological adjustments being as the substantia nigra pars compacta (SNpc), thalamus,
exceeded, in any of the systems involved in the exercise (8). striatum, nucleus accumbens, hippocampus and hypothal-
Thus, more recent theoretical models for explaining fatigue amus. The release of 5-HT into the synaptic cleft leads
highlight the involvement of the brain in this process. to the binding of the neurotransmitter to one of its fifteen
The central factors associated with fatigue consist of a receptors (divided into 7 families), thus triggering physio-
number of changes observed in the efferent neurons that logical responses (22).
alter the recruitment of motor units (9), with some of these Experiments conducted in mice have provided evi-
changes resulting from altered brain neurochemistry (10). dence that exercise changes the TRP levels, as brain
To differentiate central factors from peripheral factors, concentrations of TRP were increased after swimming to
studies usually compare the individual’s ability to generate fatigue (23). The first direct evidence of the involvement
force voluntarily in relation to the force generated by a of 5-HT in modulating fatigue was provided by studies
supra-maximal electrical stimulus applied to the nerve that observed increases in TRP concentrations in both the
trunk or intramuscular nerve branches of an active muscle plasma and brain, accompanied by increased 5-HT con-
during a voluntary contraction (i.e., the twitch interpolation centrations in the brain of rats subjected to moderate
technique) (11). In these experiments, the evidence for the intensity exercise (24,25). The ‘‘central fatigue hypoth-
involvement of central factors on fatigue is provided when esis’’ was proposed with 5-HT as the modulator of fatigue
force generated by the application of an electrical stimulus (26), because increased CNS concentrations of this
exceeds the force generated during voluntary contrac- neurotransmitter during exercise would promote increased
tions, thereby indicating that some motor units have not lethargy and higher perceived exertion, likely by modifying
been recruited voluntarily. Despite the different concepts the tolerance to pain or discomfort, which would limit
involving the process of fatigue (central and peripheral), mental and physical performances (9). Since then, to
this classification might be useful only for didactic and better understand the ‘‘central fatigue hypothesis’’,
methodological issues, because the brain and skeletal different nutritional and pharmacological manipulations
muscles have nervous connections between each other have been carried out in different experimental models to
that are highly activated during exercise and, therefore, increase or decrease 5-HT concentrations in the CNS.
could be relevant for the integration of afferent and In humans, the nutritional and pharmacological treat-
efferent signals that modulate fatigue (2). ments are given peripherally, usually by oral ingestion of
Several recent studies have investigated the cen- supplements or drugs, which can be a confounding factor
tral origin of fatigue, which appears to be associated with that would explain the different results obtained in differ-
the activity of several neurotransmitters, including seroto- ent studies, as the gastrointestinal tract expresses 5-HT
nin (5-HT) (12,13), dopamine (DA) (14,15), acetylcholine receptors (22) and may be the first site affected by these
(16), angiotensin II (17), noradrenaline (NA) (18,19) and treatments.

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Pharmacological manipulations of the activity of 5-HT changes in performance are probably due to the action of
in the CNS induced changes in physical performance, drugs on the 5-HT system in the CNS.
which supports the theory of participation of this neuro- The involvement of 5-HT in the fatigue process has
transmitter in the central fatigue mechanisms. In studies been studied by our research group since the early
with exercising rats, administration of drugs that increase 2000s and our experiments confirm the involvement
serotonergic activity (agonists of 5-HT receptors) decreased of this neurotransmitter in the modulation of fatigue.
performance, while inhibitors of serotonergic activity (recep- Increasing the levels of central TRP by amino acid injec-
tor antagonists) increased performance (Table 1). Such tion directly into the cerebral ventricles reduces the time
changes in performance were not accompanied by periph- to fatigue in rats subjected to moderate intensity treadmill
eral changes in a range of variables including muscle and running (12,16,29,30). The performance reduction caused
liver concentrations of glycogen and blood concentra- by intracerebroventricular (icv) TRP was remarkable,
tions of glucose (27,28). These findings suggest that the and the exercise duration was 60–70% lower after TRP

Table 1. Impact of different pharmacological/nutritional manipulations of the serotonergic system on physical performance in laboratory
rodents.

Study Manipulation Exercise protocol Performance

Bailey et al., ip injection of 1.0 mg/kg of quipazine dimaleate Exhausting, constant-speed quipazine dimaleate: k
1993 (27) (a 5-HT agonist) or 1.5 mg/kg of LY 53857 treadmill running at 20 m/min LY 5385: m
(a 5-HT antagonist), immediately before (5% grade)
the exercise

Calders et al., ip injection of 30 mg of BCAA 5 min before Exhausting, constant-speed m

1997 (50) the exercise. BCAA prevent the entry of free treadmill running at 20 m/min
L-TRP into the brain and, thus, decrease the (8% grade)
brain synthesis of 5-HT

Min et al., ip injection of Red ginseng (Paeonia radix) extract, Exhausting, constant-speed 10 mg/kg: m
2003 (33) which reduces the number of 5-HT-positive cells in treadmill running at 20 m/min that 50 mg/kg: m
the dorsal raphe, once a day for 5 consecutive was performed on the 5th day of 100 mg/kg: m
days. The ginseng was given at three different the experiment (a dose-dependent effect)
doses: 10, 50, and 100 mg/kg

Soares et al., icv injection of 20.3 mM of L-TRP, a precursor for Fatiguing, constant-speed k
2003 (13); 2004 5-HT synthesis, immediately before the exercise treadmill running at 18 m/min
(30); 2007 (29) (5% grade) at 23 ± 2°C

Rodrigues et al., icv injection of 5  10–3 M of physostigmine, a drug Fatiguing, constant-speed 2

2009 (16) that blocks the running-induced increase in 5-HT in treadmill running at 20 m/min
the preoptic area, immediately before the exercise (5% grade) at 23 ± 2°C

Leite et al., icv injection of 60 nmol of losartan immediately Fatiguing, constant-speed k

2010 (32) before the exercise. This drug increases the treadmill running at 18 m/min
5-HT-to-DA ratio in the hypothalamus. (5% grade) at 22 ± 2°C

Falavigna et al., Trained rats ingested a diet supplemented with Swimming exhaustion test, with 3.57%: m
2012 (51) 3.57% BCAA or 4.76% BCAA during B6 weeks a water temperature of 32°C 4.76%: k

Cordeiro et al., ip injections of 100 mg
kg–1
day–1 of p-CPA, Fatiguing, constant-speed ip p-CPA + icv saline: 2
2014 (12) a drug that selectively depletes cerebral 5-HT, treadmill running at 18 m/min ip p-CPA + icv TRP: 2
on each of the three days before the trial. These (5% grade) at 23°C
ip injections were associated with an icv injection
of saline or 20.3 mM of L-TRP immediately before
the exercise

5-HT: serotonin; BCAA: branched-chain amino acids; DA: dopamine; icv: intracerebroventricular; ip: intraperitoneal; L-TRP: L-tryptophan;
p-CPA: para-chlorophenylalanine; 2: no changes in physical performance; m: improved performance; k: impaired performance.

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administration, compared with the controls (Figure 1)

(12,30).
To confirm that TRP administration reduced physical
performance by stimulating 5-HT synthesis, we blocked
the action of tryptophan hydroxylase with systemic admin-
istration of the inhibitor para-chlorophenylalanine (p-CPA).
Rats treated with p-CPA showed no reduction of the time to
fatigue after icv administration of TRP, confirming that the
ergolytic action caused by increased central TRP was a
consequence of the conversion of the amino acid to 5-HT,
and excluding the direct participation of this amino acid in
the modulation of fatigue (Figure 1) (12).
In addition to its direct effects on behavior, 5-HT can
modulate fatigue by changes in regulation of body tempera-
ture. Increased central TRP availability reduces mechanical
efficiency in rats, leading to an increase in the heat storage
rate (i.e., the speed at which heat is stored in the body core)
and a reduction in time to fatigue (13,30). Indeed, increased Figure 2. Physical performance is associated with central con-
5-HT concentration in the preoptic area, a brain area that centrations of serotonin (5-HT) in rats. The figure shows the
controls the autonomic thermoeffectors (31), induces higher significant correlation between the time to fatigue and 5-HT
concentrations in the preoptic area in rats that received an
heat storage rate and reduces performance following icv
intracerebroventricular injection of 2 mL tryptophan (TRP, black
injection of TRP (Figure 2) (29). These findings were circles) or saline (SAL, white circles). This figure is reprinted with
permission from Soares et al., 2007 (29).

corroborated by blocking the angiotensin AT1 receptors

in the CNS, which raised the concentration of 5-HT in
the preoptic area, increased the heat storage rate and
lowered the performance of rats (32). On the other hand,
stimulation of the central cholinergic system increased
cutaneous heat dissipation in rats, attenuating hyperther-
mia induced by exercise and this lower thermal strain was
related to a decrease in 5-HT concentration in the preoptic
area (16). Together, these results suggest that 5-HT,
acting in the preoptic area, can accelerate exercise cessa-
tion, by modulating thermoregulatory mechanisms.
Interestingly, when evaluating the effects of treatment
with p-CPA (12), we noticed that rats began to dissipate
heat through the skin more rapidly and exhibited less
increase of core temperature during exercise. Surprisingly,
the lowest thermoregulatory strain caused by the decreased
central synthesis of 5-HT was not associated with an increased
performance (12). These data are not in agreement with the
results obtained in studies that subjected rats to acupunc-
ture or treated them with medicinal plants. The use of such
treatments induced ergogenic effects that were associated
Figure 1. The pharmacological blockade of serotonin synthesis
prevents the reduction in physical performance induced by central
with decreased brain 5-HT metabolism (33,34).
administration of the serotonin precursor, tryptophan (TRP). The All the findings reported so far have been obtained with
figure shows the effect of intracerebroventricular (icv) injections of laboratory rodents, which represent a powerful experimen-
TRP or saline (SAL) on time to fatigue in rats pretreated with tal model to manipulate brain neurochemistry by locally
intraperitoneal (ip) SAL or p-chlorophenylalanine (p-CPA) and that administering drugs with agonist and antagonist effects.
underwent submaximal physical exercise until they were fatigued. However, methodological and ethical issues limit the under-
Data are reported as means±SE. The number of animals is
standing of the involvement of central neurotransmitters in
indicated in parentheses. #Po0.05, significantly different from
SAL ip + SAL icv; yPo0.001, significantly different from SAL fatigue in humans. Even modern experimental approaches,
ip + TRP icv. This figure is reprinted with permission from such as positron emission tomography and near-infrared
Cordeiro et al., 2014 (12). spectroscopy, fail in revealing the phenotype of the activated

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neurons, despite the fact that these approaches allow the As it is not possible to directly measure the activity of
evaluation of active brain areas in humans under several neurotransmitters in humans, the blood concentrations of
conditions. Due to ethical issues, it is not allowed to some pituitary hormones [prolactin (PRL), adrenocortico-
administer drugs and amino acids directly into the brain of tropin, and growth hormone] have been used as indicators
humans; therefore, such substances have to be given of CNS neurotransmitter activity, as both the 5-HT and DA
systemically, which adds a number of confounding factors in modulate the secretion of these hormones (37). Eleva-
studies, including intestinal absorption of administered tions in plasma concentrations of PRL were observed in
substances, the degradation of these substances in the individuals performing prolonged exercise in a hot environ-
vascular periphery and the ability of these substances to ment, but not in a temperate environment (38). This increase
cross the blood-brain barrier. As a result of the many in plasma concentration of PRL suggests increased seroto-
confounding factors, studies using dietary manipulations nergic activity and/or reduction of the dopaminergic activity
to increase the availability of central TRP in humans in response to increased core temperature in the hot
show conflicting results regarding physical performance, environment (39). Such changes are likely to occur in the
with reports of increases (35) or no change (36) in per- hypothalamus, as 5-HT stimulates and DA inhibits the
formance (Table 2). Nevertheless, human studies are still release of PRL from the anterior pituitary lactotrophs (40).
essential to determine whether the findings obtained in Moreover, increases in serum concentrations of 5-HT and
studies in mice or rats are indeed applicable to human PRL were observed after incremental-intensity exercise to
physiology. fatigue, both in temperate and hot/humid environments.

Table 2. Impact of different pharmacological/nutritional manipulations of the serotonergic system on physical performance in humans.

Study Manipulation Exercise protocol Performance

Segura and Ingestion of 2 capsules, each containing Exhausting, constant-speed treadmill m

Ventura, 1988 (35) 150 mg of L-TRP, on the night before the test, running at 80% VO2MAX; ambient
at breakfast, lunch time and 1 h before the test temperature was set at 26°C

van Hall et al., Ingestion of drinks that contained L-TRP Cycling at a constant intensity that L-TRP
1995 (36) (3 g/L) or BCAA at two doses (6 and 18 g/L). corresponded to 70–75% of the WMAX –3 g/L: 2
These drinks were ingested during exercise until exhaustion BCAA
–6 g/L: 2
–18 g/L: 2

Struder et al., Ingestion of 21 g and 7 g of BCAA 15 min Cycling at constant intensity (256.0 ± BCAA: 2
1998 (42) before the test and after 60 min of exercise, 19.5 W) that corresponded to a blood Paroxetine: k
respectively, or ingestion of 20 mg of lactate level of 2.0 mmol/L until fatigue
paroxetine, a selective 5-HT reuptake inhibitor,
5 h before the test

Meeusen et al., Ingestion of 2 capsules containing 20 mg A time trial that required the subjects to 2
2001 (44) of fluoxetine, a selective 5-HT reuptake cycle a predetermined amount
inhibitor, on the night before and the of work (equal to 90 min at 65% WMAX)
morning of the test

Roelands et al., Ingestion of 2 capsules containing 10 mg A time trial that required the subjects to 18°C: 2
2009 (45) of citalopram, a selective 5-HT reuptake cycle a predetermined amount of work 30°C: 2
inhibitor, on the evening before and the equal to 30 min at 75% WMAX; this
morning of the test exercise was performed at 18°C
(temperate) and 30°C (hot conditions)

Teixeira-Coelho Subjects with lower and higher aerobic Cycling at a constant intensity that Lower: 2 (3 doses)
et al., 2014 (43) capacities ingested a capsule containing corresponded to 70–75% of the maximal Higher:
10, 20, or 40 mg of paroxetine 4.5 h power output. Ambient temperature was –10 mg: 2
before the test controlled at 21.4°C –20 mg: k
–40 mg: 2

5-HT: serotonin; BCAA: branched-chain amino acids; L-TRP: L-tryptophan; VO2MAX: maximal oxygen uptake; WMAX: maximal workload;
2: no changes in physical performance; m: improved performance; k: impaired performance.

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There was an inverse correlation between the increase in the central serotonergic activity and fatigue during pro-
5-HT and physical performance in the warm environment, longed exercise in humans. Contradicting the results
indicating a possible role of this neurotransmitter in the reported for subjects at rest, pharmacological stimulation
fatigue process, primarily in conditions of environmental heat of the serotonergic system decreased the time to fatigue in
stress (41). However, pharmacological manipulations to volunteers with higher aerobic capacity compared to the
change the brain 5-HT concentrations in humans have placebo condition, while stimulation of the serotonergic
produced divergent responses, with some studies showing a system did not affect the time to fatigue in the group with
decrease in performance after administration of selective lower aerobic capacity (Figure 3) (43). The results of this
serotonin reuptake inhibitors (42,43), while other studies study suggest that the serotonergic activity of individuals
have not observed this effect (44,45). with higher aerobic capacity does not have an attenuated
Not only higher 5-HT concentrations, but also the response during exercise compared to the activity of
sensitivity of receptors stimulated by 5-HT can modulate individuals with lower aerobic capacity.
feelings of fatigue during prolonged exercise. It has been Relying on the ‘‘central fatigue hypothesis’’, several
hypothesized that aerobic training modulates sensitivity of studies have tried to delay fatigue by preventing the
5-HT receptors in laboratory rodents (46) and humans increase of 5-HT in the CNS. One of the main strategies
(47,48), causing desensitization (downregulation) of these used for this purpose is nutritional supplementation with
receptors. Notably, this decreased sensitivity in rats was branched-chain amino acids (BCAA). Supplementation
more evident in response to vigorous physical training of these amino acids reduces entry of free TRP into
compared to moderate training (46). The findings of two of the CNS, because the BCAA and TRP compete for the
these three studies (46,47) suggest that trained people same transport system across the blood-brain barrier. In a
may be more resistant to fatigue not only by genotypic recent study, supplementation with BCAA before exercise
characteristics, but also by decreased receptor sensitivity performed to fatigue tended to reduce the concentration
to 5-HT, among other factors. This reduction in sensitivity of 5-HT in blood samples in the treated group compared
to 5-HT and the mechanisms involved in the process are to the control group (49). In rats, intraperitoneal treatment
still not fully elucidated, mainly due to methodological diffi- with BCAA prior to exercise increased the time to fatigue
culties related to the study of monoamines in the CNS in (50). Interestingly, Falavigna et al. (51) observed that
humans. Moreover, it is important to note that most studies the effect of BCAA on time to fatigue appears to be
have investigated sensitivity changes of serotonergic activity dose-dependent, as ingestion of smaller and larger quan-
of trained individuals when they were at rest, indicating the tities of the supplement improved and reduced performance,
need to evaluate this response while exercising. respectively (Table 1). The higher BCAA dose promoted
A recent study in our laboratory investigated the hyperammonemia, which explains the reduction in perfor-
influence of aerobic capacity on the relationship between mance. Regarding data obtained with humans, some

Figure 3. The inhibition of serotonin reuptake affects physical performance in the subjects with higher aerobic capacity but not in those
with lower aerobic capacity. The figure shows the time to fatigue by the subjects with lower (panel A) and higher (panel B) aerobic
capacity during cycling at 60% of their maximal power output. Each subject participated in four experimental trials with the following drug
conditions: placebo and 10, 20, and 40 mg of paroxetine. Data are reported as means±SE. *Po0.05, significantly different from
individuals with low aerobic capacity. #Po0.05, significantly different from the placebo. This figure is reprinted with permission from
Teixeira-Coelho et al. 2014 (43).

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studies have shown that BCAA intake can influence the system is related to the development of fatigue through
physical and mental performances of healthy individuals modulation circuits associated with the thermoregula-
(51–55). In contrast, athletes who were supplemented with tory and motor control as well as motivation and reward
amino acids, including BCAA, before and during participa- mechanisms (37,65,66).
tion in an ultramarathon (100 km) showed no improvement During exercise, the increase in the activity of the
in performance (56). This result is corroborated by several dopaminergic system in the preoptic area seems to influence
other studies that have shown no effects on fatigue induced tolerance to heat stress. In rats, both the icv administration
by supplementation with these amino acids during an of DA (15), and the intraperitoneal injection of bupropion –
incremental-intensity exercise in a temperate environment a dual DA/NA reuptake inhibitor (67) – resulted in ergogenic
(57) or prolonged exercise in temperate (36,42) and warm effects (Table 3). In these experiments, the intensification of
(58,59) environments. the dopaminergic activity allowed the rats to tolerate higher
In summary, studies in rats and humans provide evi- core temperatures before stopping exercise. It is noteworthy
dence that central serotonergic activity is related to fatigue that the reverse is also true as rats treated with DA antago-
during prolonged exercise. However, the results obtained nists seemed to tolerate a smaller increase in core tempera-
in human studies are still quite controversial and many ture and therefore exhibited a lower time to fatigue (68).
issues need clarification, such as the mechanisms under- In a recent study, intraperitoneal administration of
lying the physiological responses modulated by 5-HT and caffeine also provided evidence of the participation of DA
the effects of physical training on the activity/sensitivity of in thermoregulatory adjustments induced by exercise and
the serotonergic system. in modulating performance, as caffeine increased the
concentration of this monoamine in the preoptic area (69).
Dopamine This increase in DA concentrations evoked by caffeine is
probably a result of inhibition of central adenosine activity,
Dopamine (DA; 3,4-dihydroxy-phenylethylamine) is which inhibits activity of the dopaminergic system. When
another neurotransmitter involved in the central fatigue treated with caffeine, rats exhibited prolonged time to
mechanisms. The first evidence of the association between fatigue and achieved higher core temperature values.
DA and exercise dates from the 1970s and 1980s in Therefore, the authors suggested that the ergogenic effect
studies with rats. Peripheral administration of ampheta- of caffeine is due to an increase in central DA concentra-
mine, a DA releaser, increased the time to fatigue (60), tion, which prevents the development of fatigue (69).
whereas neuronal injury in dopaminergic pathways reduced The main hypothesis is that the DA in the preoptic area
performance (61). blocked the signal for exercise cessation that resulted
DA is synthesized from the amino acid tyrosine that from the thermal overload, thereby increasing the toler-
crosses the blood-brain barrier, is transformed into L-3,4- ance to exertional heat strain (15,67). DA is likely involved
dihydroxyphenylalanine (L-DOPA) by tyrosine hydroxylase in cutaneous heat dissipation, as blockade of CNS dopa-
and then, to DA by dopadecarboxylase. The conversion mine activity with SCH23390 (D1 receptor antagonist) and
mediated by tyrosine hydroxylase, which is stimulated by eticlopride (D2 receptor antagonist) prolonged hyperther-
calcium, is considered the limiting step of the synthesis mia after performing a fatiguing, incremental speed exercise,
of this monoamine (62). The main dopaminergic efferent without prolonging metabolic activation (68).
neurons originate in the SNpc and ventral tegmental area The relationship between physical performance and DA
(VTA) with projections to striatal structures, and to cortical, has also been investigated in experiments with humans
limbic and hypothalamic areas. The major efferent path- (Table 3). Administration of bupropion prolonged the time to
ways are the nigrostriatal (SNpc projections to the striatum), fatigue during an exercise protocol in a cycle ergometer
the mesocorticolimbic (VTA projections to the cortical and with constant power output, followed by an ‘‘against the
limbic regions) and the nigro-hypothalamic (SNpc projec- clock’’ (time-trial) protocol, both performed in a hot environ-
tions to the hypothalamus) pathways (63). DA is released ment (30°C). Improved performance was not observed
from the terminal nerve and binds to one of five DA during the same exercise in a temperate environment
receptors, which are divided into two families: D1-like (18°C) (14). Because bupropion is a dual DA/NA reuptake
(containing D1 and D5 receptors) and D2-like (with D2, inhibitor, it was imperative to understand the role of each
D3 and D4 receptors) (62). neurotransmitter on fatigue. To achieve this purpose, the
The augmented activity of the dopaminergic system in cyclists were given methylphenidate (20 mg), a specific
response to exercise initiation appears to be due to an inhibitor of DA reuptake (70). In this experiment, the
increase in the central levels of calcium, which increases subjects treated with methylphenidate showed improved
the activity of tyrosine hydroxylase through the activation performance and a greater increase in core temperature at
of the calcium-calmodulin system (64). In contrast, the 30°C, without changing their rating of perceived exertion
decrease in DA concentration that occurs as exercise (70). In fact, the higher tolerance to heat stress suggests an
continues likely results from the inhibitory effects of 5-HT. important effect of DA in motivation and fatigue, but it favors
Evidence indicates that the activity of dopaminergic the occurrence of intestinal permeability and thus may

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Table 3. Impact of different pharmacological/nutritional manipulations of the dopaminergic system on physical performance in both
laboratory rodents and humans.

Study Manipulation Exercise protocol Performance

Laboratory rodents
Gerald, 1978 (60) ip injection of 2 doses of amphetamine, Exhausting, constant-speed (10.7– 2.5 mg/kg: m
a DA releaser, prior to exercise 26.8 m/min, 8% grade) treadmill running 10.0 mg/kg: k

Heyes et al., ip injection of different doses of Exhausting, constant-speed (36.0 m/min, 1 mg/kg: 2
1985 (61) apomorphine, a non-selective DA agonist 0% grade) treadmill running 2 mg/kg: m

Hasegawa et al., ip injection of 17 mg/kg of bupropion, Exhausting, constant-speed (26 m/min) m

2008 (67) a dual DA/NA reuptake inhibitor, 20 min treadmill running at 30°C
before the exercise

Balthazar et al., icv injection of 5  10–3 M (10 nmol) of DA Fatiguing, incremental-speed running: initial m
2009 (15) solution immediately before the exercise speed of 10 m/min (5% grade), which was
increased by 1 m/min every 3 min at 22 ± 1°C

Balthazar et al., icv injection of 5  10–3 M (10 nmol) of Fatiguing, incremental-speed running: initial SCH-2239: k
2010 (68) SCH-23390, a D1 antagonist or 5  10–3 M speed of 10 m/min (5% grade), which was Eti: k
(10 nmol) of Eti, a D2 antagonist increased by 1 m/min every 3 min at 22 ± 2°C
immediately before the exercise

Zheng et al., ip injection of 10 mg/kg caffeine 60 min Fatiguing, constant-speed (18 m/min, m
(2016) (69) before the exercise. Caffeine promotes DA 5% grade) treadmill running at 23°C
release in the preoptic area and anterior
hypothalamus
Humans
Watson et al., Ingestion of 2 capsules containing 300 mg A time trial that required the subjects to cycle a 18°C: 2
2005 (14) of bupropion: one on the night before and predetermined amount of work equal to 30 min 30°C: m
the other taken upon waking on the at 75% WMAX; this exercise was performed at
morning of the trial 18°C (temperate) and 30°C (hot conditions)

Roelands et al., Ingestion of a capsule containing Same exercise protocol as in Watson et al. 18°C: 2
2008 (70) 20 mg of methylphenidate, a DA reuptake (2005) (14). The exercise was performed at 30°C: m
inhibitor, 1 h before the start of trial 18°C and 30°C

5-HT: sertononin; DA: dopamine; Eti: eticlopride solution; icv: intracerebroventricular; ip: intraperitoneal; NA: noradrenaline; WMAX:
maximal workload; 2: no changes in physical performance; m: improved performance; k: impaired performance.

represent a risk to health (4). It is important to note that physical performance and modified hormone concentra-
increased performance in humans treated with an inhibitor tions at both environments, thereby indicating a central
of DA reuptake was observed in warm environments (30°C), effect of the drug (19). Collectively, these findings indicate
but not in temperate environments (18°C) (70). This is an that the noradrenergic system decreases performance
important difference between the findings in experiments and confirm results from previous studies that increased
with rats and human beings, since central injection of DA DA activity is important in improving performance.
induced an increased time to fatigue in rats running at 22°C The dopaminergic nigrostriatal pathway formed by
(15), which represents a temperate environmental for rats. the SNpc projections into the striatum is also associated
To clarify the role of NA on the ergogenic effects of with fine adjustment of movement (66,71). In this circuitry,
bupropion, cyclists ingested reboxetine, a NA reuptake DA modulates the direct and indirect pathways for the
inhibitor, before being subjected to time trials at 18° and movement control, through interaction with D1 and D2
30°C (19). Of note, NA is synthesized from the amino acid receptors, respectively (66). As increased DA in the
tyrosine (same pathway as for DA synthesis) and also CNS attenuated the decrease in mechanical efficiency
influences motivation and motor behavior, thereby playing during exercise (15), it is possible that the dopaminergic
an important role on fatigue (10). Reboxetine reduced system adjusts motor responses that influence physical

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Serotonin, dopamine and fatigue during physical exercise 9/13

(76), as well as improved walking patterns and body

stability after treadmill training (77). It is possible that this
increase in the motor performance after the exercise
accompanied by attenuation of fatigue occurs as a result
of an increased blood calcium concentration, which could
lead to increases in dopaminergic activity (64).
From analysis and interpretation of all these studies,
we conclude that the dopaminergic system influences
physical performance by acting on different neural path-
ways, which include the control of movement, thermo-
regulation, perceived exertion, motivation and reward.
Moreover, chronic exercise modulates the activity of
this system, even in pathological conditions, such as
Parkinson’s disease.

Interactions between the serotonergic and

dopaminergic systems for determining
Figure 4. Concentrations of dopaminergic variables in the
caudate–putamen at rest and after moderate-intensity exercise fatigue
(ME) in rats with low (LP), standard (SP) and high (HP) per-
formances. The figure shows the concentrations of 3,4-dihydroxy- As previously discussed, the development of fatigue is
phenylacetic acid-to-dopamine (DOPAC/DA) ratio. Data are reported influenced by the neurotransmitters 5-HT and DA (Figure 5).
as means±SE. *Po0.05, **Po0.01 compared to rest.+Po0.05 In general, the activation of dopaminergic and serotonergic
compared to LP. #Po0.05 compared to SP. This figure is
reprinted with permission from Rabelo et al., 2015 (72).
systems increased and decreased, respectively, the physi-
cal performance. However, these modulatory effects on
fatigue may result from an interaction between these two
neurotransmitters during exercise. There is evidence of
performance. Rats with high intrinsic predisposition to 5-HT release inhibition by DA, as indicated by experiments
exercise exhibited higher basal dopaminergic activity in the showing increased and decreased serotonergic activity with
caudate-putamen (dorsal striatum) (Figure 4), which could the use of DA receptor antagonists and agonists, respec-
make them more efficient during treadmill running (72). This tively (78). These findings were expanded later, when an
is a hypothesis to be tested in future studies. In addition to inhibitory reciprocal relationship between the dopaminergic
this motor response, because the activity of the striatal and serotonergic systems was demonstrated (27). These
neurons is associated with positive reinforcement for results allowed the reformulation of the ‘‘Central Fatigue
exercise (71), it is also possible that increased striatal Hypothesis’’, which is now based on the relationship
dopaminergic activity might induce greater motivation for between 5-HT and DA. According to Davis and Bailey (79),
physical exercise (72). Moreover, animals with brain lesions
in this circuitry develop a hypoactivity frame due to the
extinction of the positive reinforcement for exercise (73).
Chronic exercise induces plasticity in the dopaminergic
pathways. These findings were observed in rodent models
of Parkinson’s disease (administration of 6-hydroxydopamine
in rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in
mice). In this condition of injury and degeneration of the
nigrostriatal pathway, chronic exercise induced neural
protection and recovery responses in the striatum, leading
to improved motor control (74,75). Following chronic exer-
cise, the motor deficit from the neuronal injury was reversed
by restoration of DA concentrations and its metabolites in
the striatum (75) and increased release of DA in the same
area (74).
Such effects of chronic exercise on motor recovery
and on the plasticity of the dopaminergic system have also
been investigated in experiments with humans. Individuals
with Parkinson’s disease have increased grip strength Figure 5. Motor and psycho-physiological effects induced by
and improved fine motor coordination after 12 weeks of monoamines in the central nervous system that modulate fatigue
training karate movements emphasizing the upper limbs during aerobic exercises.

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Serotonin, dopamine and fatigue during physical exercise 10/13

fatigue is due to an increase in serotonergic activity and a the caudate-putamen (89). Use of a running wheel for
decrease in dopaminergic activity. During physical exertion, 6 weeks increased the expression of the mRNA for 5-HT1A,
a kinetic ‘‘pattern’’ develops in the activity of both systems, an autoreceptor that inhibits the synthesis and release
with gradual increases in serotonergic and dopaminergic of 5-HT, in the raphe (90); six weeks of wheel running
activities being observed during the initial period of exercise. also increased the mRNA for tyrosine hydroxylase in
However, as exercise cessation approaches, the dopami- the SNpc and for D2 receptors in the caudate-putamen
nergic activity returns to basal values but the serotoniner- (66). When taken together, these modulations tend to
gic activity remains high (15,27,65,72). enhance the activity of the dopaminergic system and to
The serotoninergic projections inhibit dopaminergic promote a concomitant down-regulation of the seroto-
function in two different brain regions: the midbrain and nergic system.
the striatum/cortex. In the midbrain, stimulation of dorsal
raphe serotonergic fibers causes the release of 5-HT in Final remarks
the SNpc (80), which is associated with a decrease in the
firing rate of dopaminergic neurons, antagonizing the Fatigue is a complex sensation involving changes in
response mediated by DA (81). In this context, selective the CNS, which integrates information related to the
inhibitors of 5-HT uptake or agonists of 5-HT1A receptors motivation to exercise, external (environmental) conditions
(at high doses) functionally inhibit nigral dopaminergic and internal conditions of the body, so as to prevent
neurons (82,83), whereas anatomical and chemical injuries extreme physical exertion that may cause irreversible
that destroy the raphe projections to the SNpc (82) or damage. This integration involves the action of neuro-
antagonists of 5-HT2 receptors (which tonically inhibit the transmitters in the CNS. In general, studies with laboratory
mesencephalic dopaminergic system) (84) cause biochem- rodents and humans indicate that increased serotonergic
ical and functional disinhibition of the dopaminergic system. activity and reduced dopaminergic activity are associated
In relation to the prosencephalon, immunohistochem- with accelerated fatigue. Further research should deter-
ical studies have shown that serotonergic neurons arising mine exactly how neurotransmitters, mainly 5-HT and DA,
in the dorsal raphe nuclei are projected via the medial modulate fatigue during exercise, as well as elucidate
forebrain bundle to the striatum and cortex (85). Stimula- whether physical training protocols induce plasticity of
tion of these raphe striatal neurons or administration of action of these neurotransmitters in order to improve
5-HT receptor agonists inhibits the neuronal firing rate in physical performance.
the striatum, presumably by decreasing release of DA in
the synaptic cleft (86). Consistent with this inhibitory effect Acknowledgements
of 5-HT on DA release, lesions of the serotonergic projec-
tions induce disinhibition of the dopaminergic system and We thank Dr. Y.S. Bakhle for editing the English in a
increase DA concentrations (87). Similar evidence exists first draft of this manuscript. This article is in memory of
for striatal control of limbic and cortical dopaminergic our friend Reinaldo Teles Paulinelli Jr. Principal investiga-
function (88). tors who co-authored the present review received financial
In addition to the evidence demonstrating the inhibitory support from the Conselho Nacional de Desenvolvimento
relationship between the two neurotransmitters and the Científico e Tecnológico (CNPq), Coordenac¸ão de Aper-
influence of this relationship in physical exercise, there feic¸oamento de Pessoal de Nível Superior (CAPES), and
is also evidence that chronic exercise triggers plasticity Fundac¸ão de Amparo à Pesquisa do Estado de Minas
in the neural pathways of 5-HT and DA (74). Physical Gerais (FAPEMIG, APQ-02125-13 and PRI-00422-17).
training decreased the sensitivity of 5-HT receptors in L.M.S. Cordeiro received a post-doctoral fellowship
rat substantia nigra (46), and prolonged the release of from FAPEMIG (BPD-00555-14). P.C.R. Rabelo and
DA following the administration of methamphetamine in M.M. Moraes received PhD fellowships from CAPES.

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