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Physical exercise-induced fatigue: the role of serotonergic and dopaminergic systems

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 pharmacological 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.

Brain; Lethargy; Monoamines; Performance; Physical activity; Reward


Introduction

Fatigue is a feeling commonly experienced in our daily lives, for example, during periods of vigorous and/or prolonged physical activity. In the sporting context, fatigue is crucial to the performance of athletes in virtually all competitive events, although the determinant factors (either physiological or psychological) for fatigue are specific to the individual events. The present review will focus on fatigue during prolonged (aerobic) exercise, thus characterizing exertion in long-distance sports athletes, including runners, cyclists and swimmers. In these conditions, the determinant factors for fatigue will depend on several aspects, such as exercise intensity and duration, environmental conditions, nutrition and the fitness level of the individual. For instance, regulation of body temperature plays an important role on fatigue during a prolonged exercise (∼60 min) at 60% of the maximal aerobic capacity in hot weather (11. Nybo L, Nielsen B. Hyperthermia and central fatigue during prolonged exercise in humans. J Appl Physiol 2001; 91: 1055–1060.).

Fatigue and exhaustion are commonly used as synonymous in the literature, including some studies cited in this review. In general, the moment at which exercise ceases is usually termed as point of exhaustion in human studies. However, the two terms may be related to different processes with distinct physiological characteristics. The feeling of fatigue appears to occur before any damage to body systems, and it is common to see the term ‘volitional fatigue’, indicating that subjects decided to stop exercising. Exhaustion can be defined as extreme fatigue, a state in which an individual may exceed his/her physiological limits and then experience a “catastrophic” failure of homeostasis (22. Noakes TD. Fatigue is a brain-derived emotion that regulates the exercise behavior to ensure the protection of whole body homeostasis. Front Physiol 2012; 3: 82, doi: 10.3389/fphys.2012.00082.
https://doi.org/10.3389/fphys.2012.00082...
). In this context, the increase of core body temperature would be less in fatigued compared to exhausted individuals. Of note, severe hyperthermia induces some impairments, such as changes in behavior, confusion, loss of coordination and awareness (33. Cheung SS, Sleivert GG. Multiple triggers for hyperthermic fatigue and exhaustion. Exerc Sport Sci Rev 2004; 32: 100–106, doi: 10.1097/00003677-200407000-00005.
https://doi.org/10.1097/00003677-2004070...
), and may favor the occurrence of heat-related disorders (44. Pires W, Veneroso CE, Wanner SP, Pacheco DA, Vaz GC, Amorim FT, et al. Association between exercise-induced hyperthermia and intestinal permeability: A systematic review. Sports Med 2017; 47: 1389–1403, doi: 10.1007/s40279-016-0654-2.
https://doi.org/10.1007/s40279-016-0654-...
). In experiments with rats, fatigue is usually defined as the moment when the animals cannot keep the pace on a treadmill during a predetermined time (55. Wanner SP, Primola-Gomes TN, Pires W, Guimaraes JB, Hudson AS, Kunstetter AC, et al. Thermoregulatory responses in exercising rats: methodological aspects and relevance to human physiology. Temperature 2015; 2: 457–475, doi: 10.1080/23328940.2015.1119615.
https://doi.org/10.1080/23328940.2015.11...
). In contrast, exhaustion is confirmed by the observation that exhausted rats lose their righting reflex (i.e., the ability to right themselves when placed on their backs) (55. Wanner SP, Primola-Gomes TN, Pires W, Guimaraes JB, Hudson AS, Kunstetter AC, et al. Thermoregulatory responses in exercising rats: methodological aspects and relevance to human physiology. Temperature 2015; 2: 457–475, doi: 10.1080/23328940.2015.1119615.
https://doi.org/10.1080/23328940.2015.11...
).

The psycho-physiological process that triggers the feeling of fatigue is complex and may result from peripheral and central factors. Peripheral fatigue is defined as the loss of force caused by processes occurring at or distal to the neuromuscular junction (66. Taylor JL, Todd G, Gandevia SC. Evidence for a supraspinal contribution to human muscle fatigue. Clin Exper Pharm Physiol 2006; 33: 400–405, doi: 10.1111/j.1440-1681.2006.04363.x.
https://doi.org/10.1111/j.1440-1681.2006...
). In a simpler way, peripheral fatigue can be thought of as fatigue within the muscle itself. Some relevant peripheral factors are specific impairments in neuromuscular transmission and impulse propagation, substrate depletion, reduction in muscle pH, dysfunction within the sarcoplasmic reticulum involving calcium release and uptake, which together impair the ability of muscle fibers to generate power (77. Davis JM. Central and peripheral factors in fatigue. J Sports Sci 1995; 13 (Spec No.): S49–S53, doi: 10.1080/02640419508732277.
https://doi.org/10.1080/0264041950873227...
).

In the past, fatigue was considered a consequence of the failure of contractile processes in muscle, mainly caused by accumulation of H+ ions. However, since the early 2000s, fatigue has been understood as a mechanism that aims to maintain the physiological integrity of the body (88. Lambert EV, St Clair Gibson A, Noakes TD. Complex systems model of fatigue: integrative homoeostatic control of peripheral physiological systems during exercise in humans. Br J Sports Med 2005; 39: 52–62, doi: 10.1136/bjsm.2003.011247.
https://doi.org/10.1136/bjsm.2003.011247...
). Signals arising from several systems are integrated in the brain during exercise in order to stop physical exertion or reduce its intensity, as a safety mechanism to prevent the limit of physiological adjustments being exceeded, in any of the systems involved in the exercise (88. Lambert EV, St Clair Gibson A, Noakes TD. Complex systems model of fatigue: integrative homoeostatic control of peripheral physiological systems during exercise in humans. Br J Sports Med 2005; 39: 52–62, doi: 10.1136/bjsm.2003.011247.
https://doi.org/10.1136/bjsm.2003.011247...
). Thus, more recent theoretical models for explaining fatigue highlight the involvement of the brain in this process.

The central factors associated with fatigue consist of a number of changes observed in the efferent neurons that alter the recruitment of motor units (99. Meeusen R, Watson P, Dvorak J. The brain and fatigue: new opportunities for nutritional interventions? J Sports Sci 2006; 24: 773–782, doi: 10.1080/02640410500483022.
https://doi.org/10.1080/0264041050048302...
), with some of these changes resulting from altered brain neurochemistry (1010. Meeusen R, Roelands B. Fatigue: Is it all neurochemistry? Eur J Sport Sci 2017: 1–10, doi: 10.1080/17461391.2017.1296890.
https://doi.org/10.1080/17461391.2017.12...
). To differentiate central factors from peripheral factors, studies usually compare the individual's ability to generate force voluntarily in relation to the force generated by a supra-maximal electrical stimulus applied to the nerve trunk or intramuscular nerve branches of an active muscle during a voluntary contraction (i.e., the twitch interpolation technique) (1111. Shield A, Zhou S. Assessing voluntary muscle activation with the twitch interpolation technique. Sports Med 2004; 34: 253–267, doi: 10.2165/00007256-200434040-00005.
https://doi.org/10.2165/00007256-2004340...
). In these experiments, the evidence for the involvement of central factors on fatigue is provided when force generated by the application of an electrical stimulus exceeds the force generated during voluntary contractions, thereby indicating that some motor units have not been recruited voluntarily. Despite the different concepts involving the process of fatigue (central and peripheral), this classification might be useful only for didactic and methodological issues, because the brain and skeletal muscles have nervous connections between each other that are highly activated during exercise and, therefore, could be relevant for the integration of afferent and efferent signals that modulate fatigue (22. Noakes TD. Fatigue is a brain-derived emotion that regulates the exercise behavior to ensure the protection of whole body homeostasis. Front Physiol 2012; 3: 82, doi: 10.3389/fphys.2012.00082.
https://doi.org/10.3389/fphys.2012.00082...
).

Several recent studies have investigated the central origin of fatigue, which appears to be associated with the activity of several neurotransmitters, including serotonin (5-HT) (1212. Cordeiro LM, Guimaraes JB, Wanner SP, La Guardia RB, Miranda RM, Marubayashi U, et al. Inhibition of tryptophan hydroxylase abolishes fatigue induced by central tryptophan in exercising rats. Scand J Med Sci Sports 2014; 24: 80–88, doi: 10.1111/j.1600-0838.2012.01464.x.
https://doi.org/10.1111/j.1600-0838.2012...
,1313. Soares DD, Lima NR, Coimbra CC, Marubayashi U. Evidence that tryptophan reduces mechanical efficiency and running performance in rats. Pharmacol Biochem Behav 2003; 74: 357–362, doi: 10.1016/S0091-3057(02)01003-1.
https://doi.org/10.1016/S0091-3057(02)01...
), dopamine (DA) (1414. Watson P, Hasegawa H, Roelands B, Piacentini MF, Looverie R, Meeusen R. Acute dopamine/noradrenaline reuptake inhibition enhances human exercise performance in warm, but not temperate conditions. J Physiol 2005; 565 (Part 3): 873–883, doi: 10.1113/jphysiol.2004.079202.
https://doi.org/10.1113/jphysiol.2004.07...
,1515. Balthazar CH, Leite LH, Rodrigues AG, Coimbra CC. Performance-enhancing and thermoregulatory effects of intracerebroventricular dopamine in running rats. Pharmacol Biochem Behav 2009; 93: 465–469, doi: 10.1016/j.pbb.2009.06.009.
https://doi.org/10.1016/j.pbb.2009.06.00...
), acetylcholine (1616. Rodrigues AG, Soares DD, Marubayashi U, Coimbra CC. Heat loss during exercise is related to serotonin activity in the preoptic area. Neuroreport 2009; 20: 804–808, doi: 10.1097/WNR.0b013e32832b8c90.
https://doi.org/10.1097/WNR.0b013e32832b...
), angiotensin II (1717. Leite LH, Santiago HP, de Almeida RS, Coimbra CC. Implications of angiotensin II in central nervous system on exercise performance. Curr Protein Pept Sci 2013; 14: 711–720, doi: 10.2174/1389203711209070672.
https://doi.org/10.2174/1389203711209070...
), noradrenaline (NA) (1818. Klass M, Duchateau J, Rabec S, Meeusen R, Roelands B. Noradrenaline reuptake inhibition impairs cortical output and limits endurance time. Med Sci Sports Exerc 2016; 48: 1014–1023, doi: 10.1249/MSS.0000000000000879.
https://doi.org/10.1249/MSS.000000000000...
,1919. Roelands B, Goekint M, Heyman E, Piacentini MF, Watson P, Hasegawa H, et al. Acute norepinephrine reuptake inhibition decreases performance in normal and high ambient temperature. J Appl Physiol 2008; 105: 206–212, doi: 10.1152/japplphysiol.90509.2008.
https://doi.org/10.1152/japplphysiol.905...
) and nitric oxide (2020. Wanner SP, Leite LH, Guimaraes JB, Coimbra CC. Increased brain L-arginine availability facilitates cutaneous heat loss induced by running exercise. Clin Exper Pharmacol Physiol 2015; 42: 609–616, doi: 10.1111/1440-1681.12407.
https://doi.org/10.1111/1440-1681.12407...
). However, considering the emphasis given to the involvement of 5-HT and DA in the development of fatigue in studies with humans or laboratory rodents, this review will focus on the role of these two neurotransmitters.

Serotonin

Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter synthesized from the amino acid tryptophan (TRP), which is transported through the blood-brain barrier by a specific carrier and is then hydroxylated by the action of tryptophan hydroxylase; this hydroxylation is the rate limiting step in the biosynthesis of 5-HT. Increased plasma levels of free TRP favor increases TRP concentrations in the central nervous system (CNS), and thus any condition that increases this amino acid in the plasma will induce increased concentrations in the CNS and hence the central biosynthesis of 5-HT (2121. Struder HK, Weicker H. Physiology and pathophysiology of the serotonergic system and its implications on mental and physical performance. Part II. Int J Sports Med 2001; 22: 482–497, doi: 10.1055/s-2001-17606.
https://doi.org/10.1055/s-2001-17606...
).

The bodies of serotonergic neurons are located in the CNS structures called the raphe nuclei. These nuclei are divided into caudal raphe, with descending projections to the spinal column, and rostral and medial raphe, which send ascending projections to various brain regions, such as the substantia nigra pars compacta (SNpc), thalamus, striatum, nucleus accumbens, hippocampus and hypothalamus. The release of 5-HT into the synaptic cleft leads to the binding of the neurotransmitter to one of its fifteen receptors (divided into 7 families), thus triggering physiological responses (2222. Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med 2009; 60: 355–366, doi: 10.1146/annurev.med.60.042307.110802.
https://doi.org/10.1146/annurev.med.60.0...
).

Experiments conducted in mice have provided evidence that exercise changes the TRP levels, as brain concentrations of TRP were increased after swimming to fatigue (2323. Barchas JD, Freedman DX. Brain amines: Response to physiological stress. Biochem Pharmacol 1963; 12: 1232–1235, doi: 10.1016/0006-2952(63)90101-1.
https://doi.org/10.1016/0006-2952(63)901...
). The first direct evidence of the involvement of 5-HT in modulating fatigue was provided by studies that observed increases in TRP concentrations in both the plasma and brain, accompanied by increased 5-HT concentrations in the brain of rats subjected to moderate intensity exercise (2424. Chaouloff F, Elghozi JL, Guezennec Y, Laude D. Effects of conditioned running on plasma, liver and brain tryptophan and on brain 5-hydroxytryptamine metabolism of the rat. Br J Pharmacol 1985; 86: 33–41, doi: 10.1111/j.1476-5381.1985.tb09432.x.
https://doi.org/10.1111/j.1476-5381.1985...
,2525. Chaouloff F, Kennett GA, Serrurrier B, Merino D, Curzon G. Amino acid analysis demonstrates that increased plasma free tryptophan causes the increase of brain tryptophan during exercise in the rat. J Neurochem 1986; 46: 1647–1650, doi: 10.1111/j.1471-4159.1986.tb01789.x.
https://doi.org/10.1111/j.1471-4159.1986...
). The “central fatigue hypothesis” was proposed with 5-HT as the modulator of fatigue (2626. Newsholme E, Acworth I, Blomstrand E. Amino-acids, brain neurotransmitters and a functional link between muscle and brain that is important in sustained exercise. In: Benzi G (Editor), Advances in myochemistry. London: John Libbey Eurotext Ltd.; 1987. p.127-133.), because increased CNS concentrations of this neurotransmitter during exercise would promote increased lethargy and higher perceived exertion, likely by modifying the tolerance to pain or discomfort, which would limit mental and physical performances (99. Meeusen R, Watson P, Dvorak J. The brain and fatigue: new opportunities for nutritional interventions? J Sports Sci 2006; 24: 773–782, doi: 10.1080/02640410500483022.
https://doi.org/10.1080/0264041050048302...
). Since then, to better understand the “central fatigue hypothesis”, different nutritional and pharmacological manipulations have been carried out in different experimental models to increase or decrease 5-HT concentrations in the CNS. In humans, the nutritional and pharmacological treatments are given peripherally, usually by oral ingestion of supplements or drugs, which can be a confounding factor that would explain the different results obtained in different studies, as the gastrointestinal tract expresses 5-HT receptors (2222. Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med 2009; 60: 355–366, doi: 10.1146/annurev.med.60.042307.110802.
https://doi.org/10.1146/annurev.med.60.0...
) and may be the first site affected by these treatments.

Pharmacological manipulations of the activity of 5-HT in the CNS induced changes in physical performance, which supports the theory of participation of this neurotransmitter in the central fatigue mechanisms. In studies with exercising rats, administration of drugs that increase serotonergic activity (agonists of 5-HT receptors) decreased performance, while inhibitors of serotonergic activity (receptor antagonists) increased performance (Table 1). Such changes in performance were not accompanied by peripheral changes in a range of variables including muscle and liver concentrations of glycogen and blood concentrations of glucose (2727. Bailey SP, Davis JM, Ahlborn EN. Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to fatigue. J Appl Physiol 1993; 74: 3006-3012.,2828. Bailey SP, Davis JM, Ahlborn EN. Serotonergic agonists and antagonists affect endurance performance in the rat. Int J Sports Med 1993; 14: 330–333, doi: 10.1055/s-2007-1021187.
https://doi.org/10.1055/s-2007-1021187...
). These findings suggest that the changes in performance are probably due to the action of drugs on the 5-HT system in the CNS.

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

The involvement of 5-HT in the fatigue process has been studied by our research group since the early 2000s and our experiments confirm the involvement of this neurotransmitter in the modulation of fatigue. Increasing the levels of central TRP by amino acid injection directly into the cerebral ventricles reduces the time to fatigue in rats subjected to moderate intensity treadmill running (1212. Cordeiro LM, Guimaraes JB, Wanner SP, La Guardia RB, Miranda RM, Marubayashi U, et al. Inhibition of tryptophan hydroxylase abolishes fatigue induced by central tryptophan in exercising rats. Scand J Med Sci Sports 2014; 24: 80–88, doi: 10.1111/j.1600-0838.2012.01464.x.
https://doi.org/10.1111/j.1600-0838.2012...
,1616. Rodrigues AG, Soares DD, Marubayashi U, Coimbra CC. Heat loss during exercise is related to serotonin activity in the preoptic area. Neuroreport 2009; 20: 804–808, doi: 10.1097/WNR.0b013e32832b8c90.
https://doi.org/10.1097/WNR.0b013e32832b...
,2929. Soares DD, Coimbra CC, Marubayashi U. Tryptophan-induced central fatigue in exercising rats is related to serotonin content in preoptic area. Neurosci Lett 2007; 415: 274–278, doi: 10.1016/j.neulet.2007.01.035.
https://doi.org/10.1016/j.neulet.2007.01...
,3030. Soares DD, Lima NR, Coimbra CC, Marubayashi U. Intracerebroventricular tryptophan increases heating and heat storage rate in exercising rats. Pharmacol Biochem Behav 2004; 78: 255–261, doi: 10.1016/j.pbb.2004.03.015.
https://doi.org/10.1016/j.pbb.2004.03.01...
). The performance reduction caused by intracerebroventricular (icv) TRP was remarkable, and the exercise duration was 60–70% lower after TRP administration, compared with the controls (Figure 1) (1212. Cordeiro LM, Guimaraes JB, Wanner SP, La Guardia RB, Miranda RM, Marubayashi U, et al. Inhibition of tryptophan hydroxylase abolishes fatigue induced by central tryptophan in exercising rats. Scand J Med Sci Sports 2014; 24: 80–88, doi: 10.1111/j.1600-0838.2012.01464.x.
https://doi.org/10.1111/j.1600-0838.2012...
,3030. Soares DD, Lima NR, Coimbra CC, Marubayashi U. Intracerebroventricular tryptophan increases heating and heat storage rate in exercising rats. Pharmacol Biochem Behav 2004; 78: 255–261, doi: 10.1016/j.pbb.2004.03.015.
https://doi.org/10.1016/j.pbb.2004.03.01...
).

Figure 1.
The pharmacological blockade of serotonin synthesis prevents the reduction in physical performance induced by central administration of the serotonin precursor, tryptophan (TRP). The figure shows the effect of intracerebroventricular (icv) injections of TRP or saline (SAL) on time to fatigue in rats pretreated with intraperitoneal (ip) SAL or p-chlorophenylalanine (p-CPA) and that underwent submaximal physical exercise until they were fatigued. Data are reported as means±SE. The number of animals is indicated in parentheses. #P<0.05, significantly different from SAL ip + SAL icv; §P<0.001, significantly different from SAL ip + TRP icv. This figure is reprinted with permission from Cordeiro et al., 2014 (1212. Cordeiro LM, Guimaraes JB, Wanner SP, La Guardia RB, Miranda RM, Marubayashi U, et al. Inhibition of tryptophan hydroxylase abolishes fatigue induced by central tryptophan in exercising rats. Scand J Med Sci Sports 2014; 24: 80–88, doi: 10.1111/j.1600-0838.2012.01464.x.
https://doi.org/10.1111/j.1600-0838.2012...
).

To confirm that TRP administration reduced physical performance by stimulating 5-HT synthesis, we blocked the action of tryptophan hydroxylase with systemic administration 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) (1212. Cordeiro LM, Guimaraes JB, Wanner SP, La Guardia RB, Miranda RM, Marubayashi U, et al. Inhibition of tryptophan hydroxylase abolishes fatigue induced by central tryptophan in exercising rats. Scand J Med Sci Sports 2014; 24: 80–88, doi: 10.1111/j.1600-0838.2012.01464.x.
https://doi.org/10.1111/j.1600-0838.2012...
).

In addition to its direct effects on behavior, 5-HT can modulate fatigue by changes in regulation of body temperature. 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 (1313. Soares DD, Lima NR, Coimbra CC, Marubayashi U. Evidence that tryptophan reduces mechanical efficiency and running performance in rats. Pharmacol Biochem Behav 2003; 74: 357–362, doi: 10.1016/S0091-3057(02)01003-1.
https://doi.org/10.1016/S0091-3057(02)01...
,3030. Soares DD, Lima NR, Coimbra CC, Marubayashi U. Intracerebroventricular tryptophan increases heating and heat storage rate in exercising rats. Pharmacol Biochem Behav 2004; 78: 255–261, doi: 10.1016/j.pbb.2004.03.015.
https://doi.org/10.1016/j.pbb.2004.03.01...
). Indeed, increased 5-HT concentration in the preoptic area, a brain area that controls the autonomic thermoeffectors (3131. Romanovsky AA. Thermoregulation: some concepts have changed. Functional architecture of the thermoregulatory system. Am J Physiol Regul Integr Comp Physiol 2007; 292: R37–R46, doi: 10.1152/ajpregu.00668.2006.
https://doi.org/10.1152/ajpregu.00668.20...
), induces higher heat storage rate and reduces performance following icv injection of TRP (Figure 2) (2929. Soares DD, Coimbra CC, Marubayashi U. Tryptophan-induced central fatigue in exercising rats is related to serotonin content in preoptic area. Neurosci Lett 2007; 415: 274–278, doi: 10.1016/j.neulet.2007.01.035.
https://doi.org/10.1016/j.neulet.2007.01...
). These findings were 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 (3232. Leite LH, Rodrigues AG, Soares DD, Marubayashi U, Coimbra CC. Central fatigue induced by losartan involves brain serotonin and dopamine content. Med Sci Sports Exerc 2010; 42: 1469–1476, doi: 10.1249/MSS.0b013e3181d03d36.
https://doi.org/10.1249/MSS.0b013e3181d0...
). On the other hand, stimulation of the central cholinergic system increased cutaneous heat dissipation in rats, attenuating hyperthermia induced by exercise and this lower thermal strain was related to a decrease in 5-HT concentration in the preoptic area (1616. Rodrigues AG, Soares DD, Marubayashi U, Coimbra CC. Heat loss during exercise is related to serotonin activity in the preoptic area. Neuroreport 2009; 20: 804–808, doi: 10.1097/WNR.0b013e32832b8c90.
https://doi.org/10.1097/WNR.0b013e32832b...
). Together, these results suggest that 5-HT, acting in the preoptic area, can accelerate exercise cessation, by modulating thermoregulatory mechanisms.

Figure 2.
Physical performance is associated with central concentrations of serotonin (5-HT) in rats. The figure shows the significant correlation between the time to fatigue and 5-HT concentrations in the preoptic area in rats that received an intracerebroventricular injection of 2 µL tryptophan (TRP, black circles) or saline (SAL, white circles). This figure is reprinted with permission from Soares et al., 2007 (2929. Soares DD, Coimbra CC, Marubayashi U. Tryptophan-induced central fatigue in exercising rats is related to serotonin content in preoptic area. Neurosci Lett 2007; 415: 274–278, doi: 10.1016/j.neulet.2007.01.035.
https://doi.org/10.1016/j.neulet.2007.01...
).

Interestingly, when evaluating the effects of treatment with p-CPA (1212. Cordeiro LM, Guimaraes JB, Wanner SP, La Guardia RB, Miranda RM, Marubayashi U, et al. Inhibition of tryptophan hydroxylase abolishes fatigue induced by central tryptophan in exercising rats. Scand J Med Sci Sports 2014; 24: 80–88, doi: 10.1111/j.1600-0838.2012.01464.x.
https://doi.org/10.1111/j.1600-0838.2012...
), 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 (1212. Cordeiro LM, Guimaraes JB, Wanner SP, La Guardia RB, Miranda RM, Marubayashi U, et al. Inhibition of tryptophan hydroxylase abolishes fatigue induced by central tryptophan in exercising rats. Scand J Med Sci Sports 2014; 24: 80–88, doi: 10.1111/j.1600-0838.2012.01464.x.
https://doi.org/10.1111/j.1600-0838.2012...
). These data are not in agreement with the results obtained in studies that subjected rats to acupuncture or treated them with medicinal plants. The use of such treatments induced ergogenic effects that were associated with decreased brain 5-HT metabolism (3333. Min YK, Chung SH, Lee JS, Kim SS, Shin HD, Lim BV, et al. Red ginseng inhibits exercise-induced increase in 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in dorsal raphe of rats. J Pharmacol Sci 2003; 93: 218–221, doi: 10.1254/jphs.93.218.
https://doi.org/10.1254/jphs.93.218...
,3434. Lim BV, Jang MH, Shin MC, Kim HB, Kim YJ, Kim YP, et al. Caffeine inhibits exercise-induced increase in tryptophan hydroxylase expression in dorsal and median raphe of Sprague-Dawley rats. Neurosci Lett 2001; 308: 25–28, doi: 10.1016/S0304-3940(01)01980-2.
https://doi.org/10.1016/S0304-3940(01)01...
).

All the findings reported so far have been obtained with laboratory rodents, which represent a powerful experimental model to manipulate brain neurochemistry by locally administering drugs with agonist and antagonist effects. However, methodological and ethical issues limit the understanding of the involvement of central neurotransmitters in fatigue in humans. Even modern experimental approaches, such as positron emission tomography and near-infrared spectroscopy, fail in revealing the phenotype of the activated neurons, despite the fact that these approaches allow the evaluation of active brain areas in humans under several conditions. Due to ethical issues, it is not allowed to administer drugs and amino acids directly into the brain of humans; therefore, such substances have to be given systemically, which adds a number of confounding factors in studies, including intestinal absorption of administered substances, the degradation of these substances in the vascular periphery and the ability of these substances to cross the blood-brain barrier. As a result of the many confounding factors, studies using dietary manipulations to increase the availability of central TRP in humans show conflicting results regarding physical performance, with reports of increases (3535. Segura R, Ventura JL. Effect of L-tryptophan supplementation on exercise performance. Int J Sports Med 1988; 9: 301–305, doi: 10.1055/s-2007-1025027.
https://doi.org/10.1055/s-2007-1025027...
) or no change (3636. van Hall G, Raaymakers JS, Saris WH, Wagenmakers AJ. Ingestion of branched-chain amino acids and tryptophan during sustained exercise in man: failure to affect performance. J Physiol 1995; 486 (Part 3): 789–794, doi: 10.1113/jphysiol.1995.sp020854.
https://doi.org/10.1113/jphysiol.1995.sp...
) in performance (Table 2). Nevertheless, human studies are still essential to determine whether the findings obtained in studies in mice or rats are indeed applicable to human physiology.

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

As it is not possible to directly measure the activity of neurotransmitters in humans, the blood concentrations of some pituitary hormones [prolactin (PRL), adrenocorticotropin, and growth hormone] have been used as indicators of CNS neurotransmitter activity, as both the 5-HT and DA modulate the secretion of these hormones (3737. Meeusen R, Watson P, Hasegawa H, Roelands B, Piacentini MF. Central fatigue: the serotonin hypothesis and beyond. Sports Med 2006; 36: 881–909, doi: 10.2165/00007256-200636100-00006.
https://doi.org/10.2165/00007256-2006361...
). Elevations in plasma concentrations of PRL were observed in individuals performing prolonged exercise in a hot environment, but not in a temperate environment (3838. Pitsiladis YP, Strachan AT, Davidson I, Maughan RJ. Hyperprolactinaemia during prolonged exercise in the heat: evidence for a centrally mediated component of fatigue in trained cyclists. Exp Physiol 2002; 87: 215–226, doi: 10.1113/eph8702342.
https://doi.org/10.1113/eph8702342...
). This increase in plasma concentration of PRL suggests increased serotonergic activity and/or reduction of the dopaminergic activity in response to increased core temperature in the hot environment (3939. Low D, Purvis A, Reilly T, Cable NT. The prolactin responses to active and passive heating in man. Exp Physiol 2005; 90: 909–917, doi: 10.1113/expphysiol.2005.031294.
https://doi.org/10.1113/expphysiol.2005....
). Such changes are likely to occur in the hypothalamus, as 5-HT stimulates and DA inhibits the release of PRL from the anterior pituitary lactotrophs (4040. Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion. Physiol Rev 2000; 80: 1523–1631.). Moreover, increases in serum concentrations of 5-HT and PRL were observed after incremental-intensity exercise to fatigue, both in temperate and hot/humid environments. There was an inverse correlation between the increase in 5-HT and physical performance in the warm environment, indicating a possible role of this neurotransmitter in the fatigue process, primarily in conditions of environmental heat stress (4141. Zhao J, Lai L, Cheung SS, Cui S, An N, Feng W, et al. Hot environments decrease exercise capacity and elevate multiple neurotransmitters. Life Sci 2015; 141: 74–80, doi: 10.1016/j.lfs.2015.09.001.
https://doi.org/10.1016/j.lfs.2015.09.00...
). However, pharmacological manipulations to change the brain 5-HT concentrations in humans have produced divergent responses, with some studies showing a decrease in performance after administration of selective serotonin reuptake inhibitors (4242. Struder HK, Hollmann W, Platen P, Donike M, Gotzmann A, Weber K. Influence of paroxetine, branched-chain amino acids and tyrosine on neuroendocrine system responses and fatigue in humans. Horm Metab Res 1998; 30: 188–194, doi: 10.1055/s-2007-978864.
https://doi.org/10.1055/s-2007-978864...
,4343. Teixeira-Coelho F, Uendeles-Pinto JP, Serafim AC, Wanner SP, de Matos Coelho M, Soares DD. The paroxetine effect on exercise performance depends on the aerobic capacity of exercising individuals. J Sports Sci Med 2014; 13: 232–243.), while other studies have not observed this effect (4444. Meeusen R, Piacentini MF, Van Den Eynde S, Magnus L, De Meirleir K. Exercise performance is not influenced by a 5-HT reuptake inhibitor. Int J Sports Med 2001; 22: 329–336, doi: 10.1055/s-2001-15648.
https://doi.org/10.1055/s-2001-15648...
,4545. Roelands B, Goekint M, Buyse L, Pauwels F, De Schutter G, Piacentini F, et al. Time trial performance in normal and high ambient temperature: is there a role for 5-HT? Eur J Appl Physiol 2009; 107: 119–126, doi: 10.1007/s00421-009-1109-3.
https://doi.org/10.1007/s00421-009-1109-...
).

Not only higher 5-HT concentrations, but also the sensitivity of receptors stimulated by 5-HT can modulate feelings of fatigue during prolonged exercise. It has been hypothesized that aerobic training modulates sensitivity of 5-HT receptors in laboratory rodents (4646. Chennaoui M, Grimaldi B, Fillion MP, Bonnin A, Drogou C, Fillion G, Guezennec CY. Effects of physical training on functional activity of 5-HT1B receptors in rat central nervous system: role of 5-HT-moduline. Naunyn Schmiedebergs Arch Pharmacol 2000; 361: 600–604, doi: 10.1007/s002100000242.
https://doi.org/10.1007/s002100000242...
) and humans (4747. Broocks A, Meyer T, Gleiter CH, Hillmer-Vogel U, George A, Bartmann U, et al. Effect of aerobic exercise on behavioral and neuroendocrine responses to meta-chlorophenylpiperazine and to ipsapirone in untrained healthy subjects. Psychopharmacology 2001; 155: 234–241, doi: 10.1007/s002130100706.
https://doi.org/10.1007/s002130100706...
,4848. Dwyer D, Flynn J. Short term aerobic exercise training in young males does not alter sensitivity to a central serotonin agonist. Exp Physiol. 2002; 87: 83–89, doi: 10.1113/eph8702176.
https://doi.org/10.1113/eph8702176...
), causing desensitization (downregulation) of these receptors. Notably, this decreased sensitivity in rats was more evident in response to vigorous physical training compared to moderate training (4646. Chennaoui M, Grimaldi B, Fillion MP, Bonnin A, Drogou C, Fillion G, Guezennec CY. Effects of physical training on functional activity of 5-HT1B receptors in rat central nervous system: role of 5-HT-moduline. Naunyn Schmiedebergs Arch Pharmacol 2000; 361: 600–604, doi: 10.1007/s002100000242.
https://doi.org/10.1007/s002100000242...
). The findings of two of these three studies (4646. Chennaoui M, Grimaldi B, Fillion MP, Bonnin A, Drogou C, Fillion G, Guezennec CY. Effects of physical training on functional activity of 5-HT1B receptors in rat central nervous system: role of 5-HT-moduline. Naunyn Schmiedebergs Arch Pharmacol 2000; 361: 600–604, doi: 10.1007/s002100000242.
https://doi.org/10.1007/s002100000242...
,4747. Broocks A, Meyer T, Gleiter CH, Hillmer-Vogel U, George A, Bartmann U, et al. Effect of aerobic exercise on behavioral and neuroendocrine responses to meta-chlorophenylpiperazine and to ipsapirone in untrained healthy subjects. Psychopharmacology 2001; 155: 234–241, doi: 10.1007/s002130100706.
https://doi.org/10.1007/s002130100706...
) suggest that trained people may be more resistant to fatigue not only by genotypic characteristics, but also by decreased receptor sensitivity to 5-HT, among other factors. This reduction in sensitivity to 5-HT and the mechanisms involved in the process are still not fully elucidated, mainly due to methodological difficulties related to the study of monoamines in the CNS in humans. Moreover, it is important to note that most studies have investigated sensitivity changes of serotonergic activity of trained individuals when they were at rest, indicating the need to evaluate this response while exercising.

A recent study in our laboratory investigated the influence of aerobic capacity on the relationship between the central serotonergic activity and fatigue during prolonged exercise in humans. Contradicting the results reported for subjects at rest, pharmacological stimulation of the serotonergic system decreased the time to fatigue in volunteers with higher aerobic capacity compared to the placebo condition, while stimulation of the serotonergic system did not affect the time to fatigue in the group with lower aerobic capacity (Figure 3) (4343. Teixeira-Coelho F, Uendeles-Pinto JP, Serafim AC, Wanner SP, de Matos Coelho M, Soares DD. The paroxetine effect on exercise performance depends on the aerobic capacity of exercising individuals. J Sports Sci Med 2014; 13: 232–243.). The results of this study suggest that the serotonergic activity of individuals with higher aerobic capacity does not have an attenuated response during exercise compared to the activity of individuals with lower aerobic capacity.

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. *P<0.05, significantly different from individuals with low aerobic capacity. #P<0.05, significantly different from the placebo. This figure is reprinted with permission from Teixeira-Coelho et al. 2014 (4343. Teixeira-Coelho F, Uendeles-Pinto JP, Serafim AC, Wanner SP, de Matos Coelho M, Soares DD. The paroxetine effect on exercise performance depends on the aerobic capacity of exercising individuals. J Sports Sci Med 2014; 13: 232–243.).

Relying on the “central fatigue hypothesis”, several studies have tried to delay fatigue by preventing the increase of 5-HT in the CNS. One of the main strategies used for this purpose is nutritional supplementation with branched-chain amino acids (BCAA). Supplementation of these amino acids reduces entry of free TRP into the CNS, because the BCAA and TRP compete for the same transport system across the blood-brain barrier. In a recent study, supplementation with BCAA before exercise performed to fatigue tended to reduce the concentration of 5-HT in blood samples in the treated group compared to the control group (4949. Kim DH, Kim SH, Jeong WS, Lee HY. Effect of BCAA intake during endurance exercises on fatigue substances, muscle damage substances, and energy metabolism substances. J Exerc Nutrition Biochem 2013; 17: 169–180, doi: 10.5717/jenb.2013.17.4.169.
https://doi.org/10.5717/jenb.2013.17.4.1...
). In rats, intraperitoneal treatment with BCAA prior to exercise increased the time to fatigue (5050. Calders P, Pannier JL, Matthys DM, Lacroix EM. Pre-exercise branched-chain amino acid administration increases endurance performance in rats. Med Sci Sports Exerc 1997; 29: 1182–1186, doi: 10.1097/00005768-199709000-00010.
https://doi.org/10.1097/00005768-1997090...
). Interestingly, Falavigna et al. (5151. Falavigna G, Alves de Araujo J Jr, Rogero MM, Pires IS, Pedrosa RG, Martins E Jr, et al. Effects of diets supplemented with branched-chain amino acids on the performance and fatigue mechanisms of rats submitted to prolonged physical exercise. Nutrients 2012; 4: 1767–1780, doi: 10.3390/nu4111767.
https://doi.org/10.3390/nu4111767...
) observed that the effect of BCAA on time to fatigue appears to be dose-dependent, as ingestion of smaller and larger quantities of the supplement improved and reduced performance, respectively (Table 1). The higher BCAA dose promoted hyperammonemia, which explains the reduction in performance. Regarding data obtained with humans, some studies have shown that BCAA intake can influence the physical and mental performances of healthy individuals (5151. Falavigna G, Alves de Araujo J Jr, Rogero MM, Pires IS, Pedrosa RG, Martins E Jr, et al. Effects of diets supplemented with branched-chain amino acids on the performance and fatigue mechanisms of rats submitted to prolonged physical exercise. Nutrients 2012; 4: 1767–1780, doi: 10.3390/nu4111767.
https://doi.org/10.3390/nu4111767...
5555. Mittleman KD, Ricci MR, Bailey SP. Branched-chain amino acids prolong exercise during heat stress in men and women. Med Sci Sports Exerc 1998; 30: 83–91, doi: 10.1097/00005768-199801000-00012.
https://doi.org/10.1097/00005768-1998010...
). In contrast, athletes who were supplemented with amino acids, including BCAA, before and during participation in an ultramarathon (100 km) showed no improvement in performance (5656. Knechtle B, Mrazek C, Wirth A, Knechtle P, Rust CA, Senn O, et al. Branched-chain amino acid supplementation during a 100-km ultra-marathon - a randomized controlled trial. J Nutr Sci Vitaminol 2012; 58: 36–44, doi: 10.3177/jnsv.58.36.
https://doi.org/10.3177/jnsv.58.36...
). This result is corroborated by several other studies that have shown no effects on fatigue induced by supplementation with these amino acids during an incremental-intensity exercise in a temperate environment (5757. Varnier M, Sarto P, Martines D, Lora L, Carmignoto F, Leese GP, et al. Effect of infusing branched-chain amino acid during incremental exercise with reduced muscle glycogen content. Eur J Appl Physiol Occup Physiol 1994; 69: 26–31, doi: 10.1007/BF00867923.
https://doi.org/10.1007/BF00867923...
) or prolonged exercise in temperate (3636. van Hall G, Raaymakers JS, Saris WH, Wagenmakers AJ. Ingestion of branched-chain amino acids and tryptophan during sustained exercise in man: failure to affect performance. J Physiol 1995; 486 (Part 3): 789–794, doi: 10.1113/jphysiol.1995.sp020854.
https://doi.org/10.1113/jphysiol.1995.sp...
,4242. Struder HK, Hollmann W, Platen P, Donike M, Gotzmann A, Weber K. Influence of paroxetine, branched-chain amino acids and tyrosine on neuroendocrine system responses and fatigue in humans. Horm Metab Res 1998; 30: 188–194, doi: 10.1055/s-2007-978864.
https://doi.org/10.1055/s-2007-978864...
) and warm (5858. Cheuvront SN, Carter R 3rd, Kolka MA, Lieberman HR, Kellogg MD, Sawka MN. Branched-chain amino acid supplementation and human performance when hypohydrated in the heat. J Appl Physiol 2004; 97: 1275–1282, doi: 10.1152/japplphysiol.00357.2004.
https://doi.org/10.1152/japplphysiol.003...
,5959. Watson P, Shirreffs SM, Maughan RJ. The effect of acute branched-chain amino acid supplementation on prolonged exercise capacity in a warm environment. Eur J Appl Physiol 2004; 93: 306–314, doi: 10.1007/s00421-004-1206-2.
https://doi.org/10.1007/s00421-004-1206-...
) environments.

In summary, studies in rats and humans provide evidence that central serotonergic activity is related to fatigue during prolonged exercise. However, the results obtained in human studies are still quite controversial and many issues need clarification, such as the mechanisms underlying the physiological responses modulated by 5-HT and the effects of physical training on the activity/sensitivity of the serotonergic system.

Dopamine

Dopamine (DA; 3,4-dihydroxy-phenylethylamine) is another neurotransmitter involved in the central fatigue mechanisms. The first evidence of the association between DA and exercise dates from the 1970s and 1980s in studies with rats. Peripheral administration of amphetamine, a DA releaser, increased the time to fatigue (6060. Gerald MC. Effects of (+)-amphetamine on the treadmill endurance performance of rats. Neuropharmacology 1978; 17:703–704, doi: 10.1016/0028-3908(78)90083-7.
https://doi.org/10.1016/0028-3908(78)900...
), whereas neuronal injury in dopaminergic pathways reduced performance (6161. Heyes MP, Garnett ES, Coates G. Central dopaminergic activity influences rats ability to exercise. Life Sci 1985; 36: 671–677, doi: 10.1016/0024-3205(85)90172-9.
https://doi.org/10.1016/0024-3205(85)901...
).

DA is synthesized from the amino acid tyrosine that crosses the blood-brain barrier, is transformed into L-3,4-dihydroxyphenylalanine (L-DOPA) by tyrosine hydroxylase and then, to DA by dopadecarboxylase. The conversion mediated by tyrosine hydroxylase, which is stimulated by calcium, is considered the limiting step of the synthesis of this monoamine (6262. Ben-Jonathan N, Hnasko R. Dopamine as a prolactin (PRL) inhibitor. Endocr Rev 2001; 22: 724–763, doi: 10.1210/edrv.22.6.0451.
https://doi.org/10.1210/edrv.22.6.0451...
). The main dopaminergic efferent neurons originate in the SNpc and ventral tegmental area (VTA) with projections to striatal structures, and to cortical, limbic and hypothalamic areas. The major efferent pathways are the nigrostriatal (SNpc projections to the striatum), the mesocorticolimbic (VTA projections to the cortical and limbic regions) and the nigro-hypothalamic (SNpc projections to the hypothalamus) pathways (6363. Koob GF, Sanna PP, Bloom FE. Neuroscience of addiction. Neuron 1998; 21: 467–476, doi: 10.1016/S0896-6273(00)80557-7.
https://doi.org/10.1016/S0896-6273(00)80...
). DA is released from the terminal nerve and binds to one of five DA receptors, which are divided into two families: D1-like (containing D1 and D5 receptors) and D2-like (with D2, D3 and D4 receptors) (6262. Ben-Jonathan N, Hnasko R. Dopamine as a prolactin (PRL) inhibitor. Endocr Rev 2001; 22: 724–763, doi: 10.1210/edrv.22.6.0451.
https://doi.org/10.1210/edrv.22.6.0451...
).

The augmented activity of the dopaminergic system in response to exercise initiation appears to be due to an increase in the central levels of calcium, which increases the activity of tyrosine hydroxylase through the activation of the calcium-calmodulin system (6464. Sutoo D, Akiyama K. Regulation of brain function by exercise. Neurobiol Dis. 2003; 13: 1–14, doi: 10.1016/S0969-9961(03)00030-5.
https://doi.org/10.1016/S0969-9961(03)00...
). In contrast, the decrease in DA concentration that occurs as exercise continues likely results from the inhibitory effects of 5-HT. Evidence indicates that the activity of dopaminergic system is related to the development of fatigue through modulation circuits associated with the thermoregulatory and motor control as well as motivation and reward mechanisms (3737. Meeusen R, Watson P, Hasegawa H, Roelands B, Piacentini MF. Central fatigue: the serotonin hypothesis and beyond. Sports Med 2006; 36: 881–909, doi: 10.2165/00007256-200636100-00006.
https://doi.org/10.2165/00007256-2006361...
,6565. Coimbra CC, Soares DD, Leite LHR. The involvement of brain monoamines in the onset of hyperthermic central fatigue. In: Zaslav KR (Editor), An international perspective on topics in sports medicine and sport injury. InTech; 2012: 275–295, doi: 10.5772/1503.
https://doi.org/10.5772/1503...
,6666. Foley TE, Fleshner M. Neuroplasticity of dopamine circuits after exercise: implications for central fatigue. Neuromolecular Med 2008; 10: 67–80, doi: 10.1007/s12017-008-8032-3.
https://doi.org/10.1007/s12017-008-8032-...
).

During exercise, the increase in the activity of the dopaminergic system in the preoptic area seems to influence tolerance to heat stress. In rats, both the icv administration of DA (1515. Balthazar CH, Leite LH, Rodrigues AG, Coimbra CC. Performance-enhancing and thermoregulatory effects of intracerebroventricular dopamine in running rats. Pharmacol Biochem Behav 2009; 93: 465–469, doi: 10.1016/j.pbb.2009.06.009.
https://doi.org/10.1016/j.pbb.2009.06.00...
), and the intraperitoneal injection of bupropion – a dual DA/NA reuptake inhibitor (6767. Hasegawa H, Piacentini MF, Sarre S, Michotte Y, Ishiwata T, Meeusen R. Influence of brain catecholamines on the development of fatigue in exercising rats in the heat. J Physiol 2008; 586: 141–149, doi: 10.1113/jphysiol.2007.142190.
https://doi.org/10.1113/jphysiol.2007.14...
) – resulted in ergogenic effects (Table 3). In these experiments, the intensification of the dopaminergic activity allowed the rats to tolerate higher core temperatures before stopping exercise. It is noteworthy that the reverse is also true as rats treated with DA antagonists seemed to tolerate a smaller increase in core temperature and therefore exhibited a lower time to fatigue (6868. Balthazar CH, Leite LH, Ribeiro RM, Soares DD, Coimbra CC. Effects of blockade of central dopamine D1 and D2 receptors on thermoregulation, metabolic rate and running performance. Pharmacol Rep 2010; 62: 54–61, doi: 10.1016/S1734-1140(10)70242-5.
https://doi.org/10.1016/S1734-1140(10)70...
).

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

In a recent study, intraperitoneal administration of caffeine also provided evidence of the participation of DA in thermoregulatory adjustments induced by exercise and in modulating performance, as caffeine increased the concentration of this monoamine in the preoptic area (6969. Zheng X, Hasegawa H. Administration of caffeine inhibited adenosine receptor agonist-induced decreases in motor performance, thermoregulation, and brain neurotransmitter release in exercising rats. Pharmacol Biochem Behav 2016; 140: 82–89, doi: 10.1016/j.pbb.2015.10.019.
https://doi.org/10.1016/j.pbb.2015.10.01...
). This increase in DA concentrations evoked by caffeine is probably a result of inhibition of central adenosine activity, which inhibits activity of the dopaminergic system. When treated with caffeine, rats exhibited prolonged time to fatigue and achieved higher core temperature values. Therefore, the authors suggested that the ergogenic effect of caffeine is due to an increase in central DA concentration, which prevents the development of fatigue (6969. Zheng X, Hasegawa H. Administration of caffeine inhibited adenosine receptor agonist-induced decreases in motor performance, thermoregulation, and brain neurotransmitter release in exercising rats. Pharmacol Biochem Behav 2016; 140: 82–89, doi: 10.1016/j.pbb.2015.10.019.
https://doi.org/10.1016/j.pbb.2015.10.01...
). The main hypothesis is that the DA in the preoptic area blocked the signal for exercise cessation that resulted from the thermal overload, thereby increasing the tolerance to exertional heat strain (1515. Balthazar CH, Leite LH, Rodrigues AG, Coimbra CC. Performance-enhancing and thermoregulatory effects of intracerebroventricular dopamine in running rats. Pharmacol Biochem Behav 2009; 93: 465–469, doi: 10.1016/j.pbb.2009.06.009.
https://doi.org/10.1016/j.pbb.2009.06.00...
,6767. Hasegawa H, Piacentini MF, Sarre S, Michotte Y, Ishiwata T, Meeusen R. Influence of brain catecholamines on the development of fatigue in exercising rats in the heat. J Physiol 2008; 586: 141–149, doi: 10.1113/jphysiol.2007.142190.
https://doi.org/10.1113/jphysiol.2007.14...
). DA is likely involved in cutaneous heat dissipation, as blockade of CNS dopamine activity with SCH23390 (D1 receptor antagonist) and eticlopride (D2 receptor antagonist) prolonged hyperthermia after performing a fatiguing, incremental speed exercise, without prolonging metabolic activation (6868. Balthazar CH, Leite LH, Ribeiro RM, Soares DD, Coimbra CC. Effects of blockade of central dopamine D1 and D2 receptors on thermoregulation, metabolic rate and running performance. Pharmacol Rep 2010; 62: 54–61, doi: 10.1016/S1734-1140(10)70242-5.
https://doi.org/10.1016/S1734-1140(10)70...
).

The relationship between physical performance and DA has also been investigated in experiments with humans (Table 3). Administration of bupropion prolonged the time to fatigue during an exercise protocol in a cycle ergometer with constant power output, followed by an “against the clock” (time-trial) protocol, both performed in a hot environment (30°C). Improved performance was not observed during the same exercise in a temperate environment (18°C) (1414. Watson P, Hasegawa H, Roelands B, Piacentini MF, Looverie R, Meeusen R. Acute dopamine/noradrenaline reuptake inhibition enhances human exercise performance in warm, but not temperate conditions. J Physiol 2005; 565 (Part 3): 873–883, doi: 10.1113/jphysiol.2004.079202.
https://doi.org/10.1113/jphysiol.2004.07...
). Because bupropion is a dual DA/NA reuptake inhibitor, it was imperative to understand the role of each neurotransmitter on fatigue. To achieve this purpose, the cyclists were given methylphenidate (20 mg), a specific inhibitor of DA reuptake (7070. Roelands B, Hasegawa H, Watson P, Piacentini MF, Buyse L, De Schutter G, et al. The effects of acute dopamine reuptake inhibition on performance. Med Sci Sports Exerc 2008; 40: 879–885, doi: 10.1249/MSS.0b013e3181659c4d.
https://doi.org/10.1249/MSS.0b013e318165...
). In this experiment, the subjects treated with methylphenidate showed improved performance and a greater increase in core temperature at 30°C, without changing their rating of perceived exertion (7070. Roelands B, Hasegawa H, Watson P, Piacentini MF, Buyse L, De Schutter G, et al. The effects of acute dopamine reuptake inhibition on performance. Med Sci Sports Exerc 2008; 40: 879–885, doi: 10.1249/MSS.0b013e3181659c4d.
https://doi.org/10.1249/MSS.0b013e318165...
). In fact, the higher tolerance to heat stress suggests an important effect of DA in motivation and fatigue, but it favors the occurrence of intestinal permeability and thus may represent a risk to health (44. Pires W, Veneroso CE, Wanner SP, Pacheco DA, Vaz GC, Amorim FT, et al. Association between exercise-induced hyperthermia and intestinal permeability: A systematic review. Sports Med 2017; 47: 1389–1403, doi: 10.1007/s40279-016-0654-2.
https://doi.org/10.1007/s40279-016-0654-...
). It is important to note that increased performance in humans treated with an inhibitor of DA reuptake was observed in warm environments (30°C), but not in temperate environments (18°C) (7070. Roelands B, Hasegawa H, Watson P, Piacentini MF, Buyse L, De Schutter G, et al. The effects of acute dopamine reuptake inhibition on performance. Med Sci Sports Exerc 2008; 40: 879–885, doi: 10.1249/MSS.0b013e3181659c4d.
https://doi.org/10.1249/MSS.0b013e318165...
). This is an important difference between the findings in experiments with rats and human beings, since central injection of DA induced an increased time to fatigue in rats running at 22°C (1515. Balthazar CH, Leite LH, Rodrigues AG, Coimbra CC. Performance-enhancing and thermoregulatory effects of intracerebroventricular dopamine in running rats. Pharmacol Biochem Behav 2009; 93: 465–469, doi: 10.1016/j.pbb.2009.06.009.
https://doi.org/10.1016/j.pbb.2009.06.00...
), which represents a temperate environmental for rats.

To clarify the role of NA on the ergogenic effects of bupropion, cyclists ingested reboxetine, a NA reuptake inhibitor, before being subjected to time trials at 18° and 30°C (1919. Roelands B, Goekint M, Heyman E, Piacentini MF, Watson P, Hasegawa H, et al. Acute norepinephrine reuptake inhibition decreases performance in normal and high ambient temperature. J Appl Physiol 2008; 105: 206–212, doi: 10.1152/japplphysiol.90509.2008.
https://doi.org/10.1152/japplphysiol.905...
). Of note, NA is synthesized from the amino acid tyrosine (same pathway as for DA synthesis) and also influences motivation and motor behavior, thereby playing an important role on fatigue (1010. Meeusen R, Roelands B. Fatigue: Is it all neurochemistry? Eur J Sport Sci 2017: 1–10, doi: 10.1080/17461391.2017.1296890.
https://doi.org/10.1080/17461391.2017.12...
). Reboxetine reduced physical performance and modified hormone concentrations at both environments, thereby indicating a central effect of the drug (1919. Roelands B, Goekint M, Heyman E, Piacentini MF, Watson P, Hasegawa H, et al. Acute norepinephrine reuptake inhibition decreases performance in normal and high ambient temperature. J Appl Physiol 2008; 105: 206–212, doi: 10.1152/japplphysiol.90509.2008.
https://doi.org/10.1152/japplphysiol.905...
). Collectively, these findings indicate that the noradrenergic system decreases performance and confirm results from previous studies that increased DA activity is important in improving performance.

The dopaminergic nigrostriatal pathway formed by the SNpc projections into the striatum is also associated with fine adjustment of movement (6666. Foley TE, Fleshner M. Neuroplasticity of dopamine circuits after exercise: implications for central fatigue. Neuromolecular Med 2008; 10: 67–80, doi: 10.1007/s12017-008-8032-3.
https://doi.org/10.1007/s12017-008-8032-...
,7171. Kravitz AV, Kreitzer AC. Striatal mechanisms underlying movement, reinforcement, and punishment. Physiology 2012; 27: 167–177, doi: 10.1152/physiol.00004.2012.
https://doi.org/10.1152/physiol.00004.20...
). In this circuitry, DA modulates the direct and indirect pathways for the movement control, through interaction with D1 and D2 receptors, respectively (6666. Foley TE, Fleshner M. Neuroplasticity of dopamine circuits after exercise: implications for central fatigue. Neuromolecular Med 2008; 10: 67–80, doi: 10.1007/s12017-008-8032-3.
https://doi.org/10.1007/s12017-008-8032-...
). As increased DA in the CNS attenuated the decrease in mechanical efficiency during exercise (1515. Balthazar CH, Leite LH, Rodrigues AG, Coimbra CC. Performance-enhancing and thermoregulatory effects of intracerebroventricular dopamine in running rats. Pharmacol Biochem Behav 2009; 93: 465–469, doi: 10.1016/j.pbb.2009.06.009.
https://doi.org/10.1016/j.pbb.2009.06.00...
), it is possible that the dopaminergic system adjusts motor responses that influence physical performance. Rats with high intrinsic predisposition to exercise exhibited higher basal dopaminergic activity in the caudate-putamen (dorsal striatum) (Figure 4), which could make them more efficient during treadmill running (7272. Rabelo PC, Almeida TF, Guimaraes JB, Barcellos LA, Cordeiro LM, Moraes MM, et al. Intrinsic exercise capacity is related to differential monoaminergic activity in the rat forebrain. Brain Res Bull 2015; 112: 7–13, doi: 10.1016/j.brainresbull.2015.01.006.
https://doi.org/10.1016/j.brainresbull.2...
). This is a hypothesis to be tested in future studies. In addition to this motor response, because the activity of the striatal neurons is associated with positive reinforcement for exercise (7171. Kravitz AV, Kreitzer AC. Striatal mechanisms underlying movement, reinforcement, and punishment. Physiology 2012; 27: 167–177, doi: 10.1152/physiol.00004.2012.
https://doi.org/10.1152/physiol.00004.20...
), it is also possible that increased striatal dopaminergic activity might induce greater motivation for physical exercise (7272. Rabelo PC, Almeida TF, Guimaraes JB, Barcellos LA, Cordeiro LM, Moraes MM, et al. Intrinsic exercise capacity is related to differential monoaminergic activity in the rat forebrain. Brain Res Bull 2015; 112: 7–13, doi: 10.1016/j.brainresbull.2015.01.006.
https://doi.org/10.1016/j.brainresbull.2...
). Moreover, animals with brain lesions in this circuitry develop a hypoactivity frame due to the extinction of the positive reinforcement for exercise (7373. Kiyatkin EA. Brain temperature responses to salient stimuli persist during dopamine receptor blockade despite a blockade of locomotor responses. Pharmacol Biochem Behav 2008; 91: 233–242, doi: 10.1016/j.pbb.2008.08.004.
https://doi.org/10.1016/j.pbb.2008.08.00...
).

Figure 4.
Concentrations of dopaminergic variables in the caudate–putamen at rest and after moderate-intensity exercise (ME) in rats with low (LP), standard (SP) and high (HP) performances. The figure shows the concentrations of 3,4-dihydroxyphenylacetic acid-to-dopamine (DOPAC/DA) ratio. Data are reported as means±SE. *P<0.05, **P<0.01 compared to rest.+P<0.05 compared to LP. #P<0.05 compared to SP. This figure is reprinted with permission from Rabelo et al., 2015 (7272. Rabelo PC, Almeida TF, Guimaraes JB, Barcellos LA, Cordeiro LM, Moraes MM, et al. Intrinsic exercise capacity is related to differential monoaminergic activity in the rat forebrain. Brain Res Bull 2015; 112: 7–13, doi: 10.1016/j.brainresbull.2015.01.006.
https://doi.org/10.1016/j.brainresbull.2...
).

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 (7474. Petzinger GM, Walsh JP, Akopian G, Hogg E, Abernathy A, Arevalo P, et al. Effects of treadmill exercise on dopaminergic transmission in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. J Neurosc. 2007; 27: 5291–5300, doi: 10.1523/JNEUROSCI.1069-07.2007.
https://doi.org/10.1523/JNEUROSCI.1069-0...
,7575. Gorton LM, Vuckovic MG, Vertelkina N, Petzinger GM, Jakowec MW, Wood RI. Exercise effects on motor and affective behavior and catecholamine neurochemistry in the MPTP-lesioned mouse. Behav Brain Res 2010; 213: 253–262, doi: 10.1016/j.bbr.2010.05.009.
https://doi.org/10.1016/j.bbr.2010.05.00...
). Following chronic exercise, the motor deficit from the neuronal injury was reversed by restoration of DA concentrations and its metabolites in the striatum (7575. Gorton LM, Vuckovic MG, Vertelkina N, Petzinger GM, Jakowec MW, Wood RI. Exercise effects on motor and affective behavior and catecholamine neurochemistry in the MPTP-lesioned mouse. Behav Brain Res 2010; 213: 253–262, doi: 10.1016/j.bbr.2010.05.009.
https://doi.org/10.1016/j.bbr.2010.05.00...
) and increased release of DA in the same area (7474. Petzinger GM, Walsh JP, Akopian G, Hogg E, Abernathy A, Arevalo P, et al. Effects of treadmill exercise on dopaminergic transmission in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. J Neurosc. 2007; 27: 5291–5300, doi: 10.1523/JNEUROSCI.1069-07.2007.
https://doi.org/10.1523/JNEUROSCI.1069-0...
).

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 and improved fine motor coordination after 12 weeks of training karate movements emphasizing the upper limbs (7676. Palmer SS, Mortimer JA, Webster DD, Bistevins R, Dickinson GL. Exercise therapy for Parkinson's disease. Arch Phys Med Rehabil 1986; 67: 741–745, doi: 10.1016/0003-9993(86)90007-9.
https://doi.org/10.1016/0003-9993(86)900...
), as well as improved walking patterns and body stability after treadmill training (7777. Herman T, Giladi N, Gruendlinger L, Hausdorff JM. Six weeks of intensive treadmill training improves gait and quality of life in patients with Parkinson's disease: a pilot study. Arch Phys Med Rehabil 2007; 88: 1154–1158, doi: 10.1016/j.apmr.2007.05.015.
https://doi.org/10.1016/j.apmr.2007.05.0...
). 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 (6464. Sutoo D, Akiyama K. Regulation of brain function by exercise. Neurobiol Dis. 2003; 13: 1–14, doi: 10.1016/S0969-9961(03)00030-5.
https://doi.org/10.1016/S0969-9961(03)00...
).

From analysis and interpretation of all these studies, we conclude that the dopaminergic system influences physical performance by acting on different neural pathways, which include the control of movement, thermoregulation, 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 fatigue

As previously discussed, the development of fatigue is influenced by the neurotransmitters 5-HT and DA (Figure 5). In general, the activation of dopaminergic and serotonergic systems increased and decreased, respectively, the physical performance. However, these modulatory effects on fatigue may result from an interaction between these two neurotransmitters during exercise. There is evidence of 5-HT release inhibition by DA, as indicated by experiments showing increased and decreased serotonergic activity with the use of DA receptor antagonists and agonists, respectively (7878. Chaouloff F, Laude D, Merino D, Serrurrier B, Guezennec Y, Elghozi JL. Amphetamine and alpha-methyl-p-tyrosine affect the exercise-induced imbalance between the availability of tryptophan and synthesis of serotonin in the brain of the rat. Neuropharmacology 1987; 26: 1099–1106, doi: 10.1016/0028-3908(87)90254-1.
https://doi.org/10.1016/0028-3908(87)902...
). These findings were expanded later, when an inhibitory reciprocal relationship between the dopaminergic and serotonergic systems was demonstrated (2727. Bailey SP, Davis JM, Ahlborn EN. Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to fatigue. J Appl Physiol 1993; 74: 3006-3012.). These results allowed the reformulation of the “Central Fatigue Hypothesis”, which is now based on the relationship between 5-HT and DA. According to Davis and Bailey (7979. Davis JM, Bailey SP. Possible mechanisms of central nervous system fatigue during exercise. Med Sci Sports Exerc 1997; 29: 45–57, doi: 10.1097/00005768-199701000-00008.
https://doi.org/10.1097/00005768-1997010...
), fatigue is due to an increase in serotonergic activity and a decrease in dopaminergic activity. During physical exertion, a kinetic “pattern” develops in the activity of both systems, with gradual increases in serotonergic and dopaminergic activities being observed during the initial period of exercise. However, as exercise cessation approaches, the dopaminergic activity returns to basal values but the serotoninergic activity remains high (1515. Balthazar CH, Leite LH, Rodrigues AG, Coimbra CC. Performance-enhancing and thermoregulatory effects of intracerebroventricular dopamine in running rats. Pharmacol Biochem Behav 2009; 93: 465–469, doi: 10.1016/j.pbb.2009.06.009.
https://doi.org/10.1016/j.pbb.2009.06.00...
,2727. Bailey SP, Davis JM, Ahlborn EN. Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to fatigue. J Appl Physiol 1993; 74: 3006-3012.,6565. Coimbra CC, Soares DD, Leite LHR. The involvement of brain monoamines in the onset of hyperthermic central fatigue. In: Zaslav KR (Editor), An international perspective on topics in sports medicine and sport injury. InTech; 2012: 275–295, doi: 10.5772/1503.
https://doi.org/10.5772/1503...
,7272. Rabelo PC, Almeida TF, Guimaraes JB, Barcellos LA, Cordeiro LM, Moraes MM, et al. Intrinsic exercise capacity is related to differential monoaminergic activity in the rat forebrain. Brain Res Bull 2015; 112: 7–13, doi: 10.1016/j.brainresbull.2015.01.006.
https://doi.org/10.1016/j.brainresbull.2...
).

Figure 5.
Motor and psycho-physiological effects induced by monoamines in the central nervous system that modulate fatigue during aerobic exercises.

The serotoninergic projections inhibit dopaminergic function in two different brain regions: the midbrain and the striatum/cortex. In the midbrain, stimulation of dorsal raphe serotonergic fibers causes the release of 5-HT in the SNpc (8080. Nedergaard S, Bolam JP, Greenfield SA. Facilitation of a dendritic calcium conductance by 5-hydroxytryptamine in the substantia nigra. Nature 1988; 333: 174–177, doi: 10.1038/333174a0.
https://doi.org/10.1038/333174a0...
), which is associated with a decrease in the firing rate of dopaminergic neurons, antagonizing the response mediated by DA (8181. Olpe HR, Koella WP. The response of striatal cells upon stimulation of the dorsal and median raphe nuclei. Brain Res 1977; 122: 357–360, doi: 10.1016/0006-8993(77)90302-X.
https://doi.org/10.1016/0006-8993(77)903...
). In this context, selective inhibitors of 5-HT uptake or agonists of 5-HT1A receptors (at high doses) functionally inhibit nigral dopaminergic neurons (8282. James TA, Starr MS. Rotational behaviour elicited by 5-HT in the rat: evidence for an inhibitory role of 5-HT in the substantia nigra and corpus striatum. J Pharm Pharmacol 1980; 32: 196–200, doi: 10.1111/j.2042-7158.1980.tb12889.x.
https://doi.org/10.1111/j.2042-7158.1980...
,8383. Arborelius LC, Chergui K, Murase S, Nomikos GG, Hook BB, Chouvet G, et al. The 5-HT sub 1A receptor selective ligands, (R)-8-OH-DPAT and (S)-UH-301, differentially affect the activity of midbrain dopamine neurons. Arch Pharmacol Naunyn-Schmiedeberg 1993; 347: 353–362, doi: 10.1007/BF00165384.
https://doi.org/10.1007/BF00165384...
), whereas anatomical and chemical injuries that destroy the raphe projections to the SNpc (8282. James TA, Starr MS. Rotational behaviour elicited by 5-HT in the rat: evidence for an inhibitory role of 5-HT in the substantia nigra and corpus striatum. J Pharm Pharmacol 1980; 32: 196–200, doi: 10.1111/j.2042-7158.1980.tb12889.x.
https://doi.org/10.1111/j.2042-7158.1980...
) or antagonists of 5-HT2 receptors (which tonically inhibit the mesencephalic dopaminergic system) (8484. Ugedo L, Grenhoff J, Svensson TH. Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition. Psychopharmacology 1989; 98: 45–50, doi: 10.1007/BF00442004.
https://doi.org/10.1007/BF00442004...
) cause biochemical and functional disinhibition of the dopaminergic system.

In relation to the prosencephalon, immunohistochemical studies have shown that serotonergic neurons arising in the dorsal raphe nuclei are projected via the medial forebrain bundle to the striatum and cortex (8585. Jacobs BL, Azmitia EC. Structure and function of the brain serotonin system. Physiol Rev 1992; 72: 165–229.). Stimulation of these raphe striatal neurons or administration of 5-HT receptor agonists inhibits the neuronal firing rate in the striatum, presumably by decreasing release of DA in the synaptic cleft (8686. Waldmeier PC, Delini-Stula AA. Serotonin - dopamine interactions in the nigrostriatal system. Eur J Pharmacol 1979; 55: 363–373, doi: 10.1016/0014-2999(79)90110-9.
https://doi.org/10.1016/0014-2999(79)901...
). Consistent with this inhibitory effect of 5-HT on DA release, lesions of the serotonergic projections induce disinhibition of the dopaminergic system and increase DA concentrations (8787. Dray AO, NR. Bromocriptine and dopamine‐receptor stimulation. J Pharm Pharmacol 1976; 28: 586–588, doi: 10.1111/j.2042-7158.1976.tb02802.x.
https://doi.org/10.1111/j.2042-7158.1976...
). Similar evidence exists for striatal control of limbic and cortical dopaminergic function (8888. Hamon M, Gozlan H, El Mestikawy S, Emerit MB, Bolanos F, Schechter L. The central 5-HT sub 1A receptors: pharmacological, biochemical, functional and regulatory properties. Ann NY Acad Sci 1990; 600: 114–129, doi: 10.1111/j.1749-6632.1990.tb16877.x.
https://doi.org/10.1111/j.1749-6632.1990...
).

In addition to the evidence demonstrating the inhibitory relationship between the two neurotransmitters and the influence of this relationship in physical exercise, there is also evidence that chronic exercise triggers plasticity in the neural pathways of 5-HT and DA (7474. Petzinger GM, Walsh JP, Akopian G, Hogg E, Abernathy A, Arevalo P, et al. Effects of treadmill exercise on dopaminergic transmission in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. J Neurosc. 2007; 27: 5291–5300, doi: 10.1523/JNEUROSCI.1069-07.2007.
https://doi.org/10.1523/JNEUROSCI.1069-0...
). Physical training decreased the sensitivity of 5-HT receptors in rat substantia nigra (4646. Chennaoui M, Grimaldi B, Fillion MP, Bonnin A, Drogou C, Fillion G, Guezennec CY. Effects of physical training on functional activity of 5-HT1B receptors in rat central nervous system: role of 5-HT-moduline. Naunyn Schmiedebergs Arch Pharmacol 2000; 361: 600–604, doi: 10.1007/s002100000242.
https://doi.org/10.1007/s002100000242...
), and prolonged the release of DA following the administration of methamphetamine in the caudate-putamen (8989. Marques E, Vasconcelos F, Rolo MR, Pereira FC, Silva AP, Macedo TR, et al. Influence of chronic exercise on the amphetamine-induced dopamine release and neurodegeneration in the striatum of the rat. Ann N Y Acad Sci 2008; 1139: 222–231, doi: 10.1196/annals.1432.041.
https://doi.org/10.1196/annals.1432.041...
). Use of a running wheel for 6 weeks increased the expression of the mRNA for 5-HT1A, an autoreceptor that inhibits the synthesis and release of 5-HT, in the raphe (9090. Greenwood BN, Foley TE, Day HE, Burhans D, Brooks L, Campeau S, et al. Wheel running alters serotonin (5-HT) transporter, 5-HT1A, 5-HT1B, and alpha 1b-adrenergic receptor mRNA in the rat raphe nuclei. Biol Psychiatry 2005; 57: 559–568, doi: 10.1016/j.biopsych.2004.11.025.
https://doi.org/10.1016/j.biopsych.2004....
); six weeks of wheel running also increased the mRNA for tyrosine hydroxylase in the SNpc and for D2 receptors in the caudate-putamen (6666. Foley TE, Fleshner M. Neuroplasticity of dopamine circuits after exercise: implications for central fatigue. Neuromolecular Med 2008; 10: 67–80, doi: 10.1007/s12017-008-8032-3.
https://doi.org/10.1007/s12017-008-8032-...
). When taken together, these modulations tend to enhance the activity of the dopaminergic system and to promote a concomitant down-regulation of the serotonergic system.

Final remarks

Fatigue is a complex sensation involving changes in the CNS, which integrates information related to the motivation to exercise, external (environmental) conditions and internal conditions of the body, so as to prevent extreme physical exertion that may cause irreversible damage. This integration involves the action of neurotransmitters in the CNS. In general, studies with laboratory rodents and humans indicate that increased serotonergic activity and reduced dopaminergic activity are associated with accelerated fatigue. Further research should determine exactly how neurotransmitters, mainly 5-HT and DA, modulate fatigue during exercise, as well as elucidate whether physical training protocols induce plasticity of action of these neurotransmitters in order to improve physical performance.

Acknowledgements

We thank Dr. Y.S. Bakhle for editing the English in a first draft of this manuscript. This article is in memory of our friend Reinaldo Teles Paulinelli Jr. Principal investigators who co-authored the present review received financial support from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo è Pesquisa do Estado de Minas Gerais (FAPEMIG, APQ-02125-13 and PRI-00422-17). L.M.S. Cordeiro received a post-doctoral fellowship from FAPEMIG (BPD-00555-14). P.C.R. Rabelo and M.M. Moraes received PhD fellowships from CAPES.

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Publication Dates

  • Publication in this collection
    2017

History

  • Received
    2 Apr 2017
  • Accepted
    25 Aug 2017
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