”serotonin-fatigue hypothesis” is clear, several seemingly well-conducted studies have failed to . brain neurotransmitter systems (Meeusen and De Meirleir. Brain neurotransmitters in fatigue and overtraining. Romain Meeusen,ab Philip Watson,b Hiroshi Hasegawa,ac Bart Roelands,a Maria F. Such a change in neurotransmission has a direct impact on fatigue. sudden and profound central fatigue in athletes due to overtraining involves hypothalamic . These parts of the brain are also critical for evaluating and regulating external.

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Relationship of the overtraining syndrome with stress, fatigue, and serotonin.

Brain neurotransmitters in fatigue and overtraining.

The requirements of the competitive sports have caused severe consequences in athletes involved in high level training. The changing braain the aesthetic standards has leaded individuals to search for physical exercises to reduce their body mass, to increase their muscular mass as well as their aerobic fitness. It is quite faatigue that athletes and non-athletes overtrainign the limits of their physical and psychological capacities causing the development of the overtraining syndrome, which is defined as the neuroendocrine disorder hypothalamohypophysialresulting from the imbalance between the demand neurotranssmitters the exercise and the possibility of assimilation of overtrqining training, causing metabolic changes with consequences comprising not only the performance, but also other physiological and emotional aspects.

The high level of physical, sociocultural and psychic stress are factors that contribute to such outcome, as well as to neuroendocrine changes caused by nutritional aspects that lead to serotoninergic fluctuations. Changes in the brain serotonin level can be associated to the occurrence of the physical fatigue, and this may be chronically settled, constituting one of the symptoms of the whole overtraining syndrome.

Deficiencies or imbalances in neurotransmitters and neuromodulators can also be caused by severe or prolonged stress. The aim of this reviewing study was to analyze those factors that synergistically contribute to the outcome of the overtraining syndrome. Los requisitos de deporte competitivo han provocado consecuencias serias en atletas involucrados en el entrenamiento de nivel alto.

Relationship of the overtraining syndrome with stress, fatigue, and serotonin

The focus given to the health services in controlling the sedentarism through the regular practice of exercises 1 and the changing in the aesthetic standards have lead individuals to search for a reduction in their body mass, to increase the muscle mass through physical exercises in addition to the traditional aerobic fitness. On the other hand, high level athletes suffer the harmful consequences that come from pressures provoked in the present context of the highly demanded sportive practice.

Primarily observed in athletes, the overtraining syndrome is characterized by metabolic changes, reduction in the athletic performance, and the response to the training in neurotrannsmitters individuals, incidence of bruises and viral and bacterial infections due to the fall in the immunological resistance, alterations in the mood, constant fatigue, etc.

Overtrainin set of signs neurotransmittsrs symptoms cause chronic fatigue in the individual, and etiology of such signs and symptoms involves the imbalance of the cerebral neurotransmitters, as well as a decrease in the serotonin levels 5-HTthat by its turn is derived from the tryptophan, an aminoacid delivered by a high-protein diet 3. It is possible that the energetic metabolism, which is secondary to the endocrine changes, be changed in the overtraining syndrome, and thus, consequently affecting the fatigue as well.

Studies have demonstrated that deficiencies or imbalances in the neurotransmitters and neuromodulators can be caused by severe or prolonged stress 4. Other factors can predispose individuals to the syndrome, such as a high number of competitions, monotony of the training, trainers and relatives’ high expectations of outcomes, the individual structure of the personality, the social environment, preexisting medical conditions, environmental factors altitude, temperature and humidityand even the lack of professional guidance as to the correct practice of the physical exercises 5.

Several situations seem to be related to the overtraining syndrome, and despite its extended list of signs and symptoms, a definitive diagnosis criterion and its biochemical-metabolic neurotranxmitters are yet to be discovered 6,7. Aiming to understand such mechanism, this reviewing work has the purpose to analyze those factors that synergistically contribute to the outcome and maintenance of the signs, symptoms, and imbalances that characterize it.

Stress can be defined within a psychological perspective as the individual perception related to the imbalance between the physical or psychological demands, and their resources to face them in an activity that is regarded important, such as, for instance, the sportive action to the athlete 8. It can be differentiated in eustressor positive stress, characterized by the mobilization of every physical and spiritual strength in a status of strong excitement causing feelings of joy, satisfaction and happiness 9and distressor negative stress, that represents a fatiguee situation to the body, which can be acute whenever it is intense, and it is installed in a quite short period of time, or chronic, whenever it is gradually installed for a longer period 8.

The term stress means the status generated by the perception of the stimulus that cause emotional excitement, and upon the perturbation of the homeostasis, it triggers an adaptation process that is characterized among other changes by an increasing adrenaline secretion, producing several systemic manifestations with physiological znd psychological disturbances It has been observed that the overtraining syndrome is generally caused by a sum of multiple stressing events in the life, such as physical training, sleep neurotransmittes, exposition to stressing environments humidity, cold, altitude, and heatand change of residence, occupational pressures, and interpersonal difficulties.

The GAS is composed by three phases: All these three phases involve hormonal responses trying to re-establish the balance. In the first phase, the body recognizes and reacts to the stressing factor s. In the resistance phase, it is already able to make the appropriate psychological adaptations with no damages.


In terms of training, the overreaching causes a temporary decrease in the body’s functioning, followed by an adaptation that overpasses the initial level of such functioning. The exhaustion phase can be reached whenever the body is under stress for a long period of time.

At this point, his defense system is overloaded causing a lack of the adaptations, and his ability as to the psychological adequacy is lost for a period of time. Although much of the overtraining symptoms are similar to the resistance and exhaustion phases of the Seyle’s GAS, this model is unable to clarify the very mechanism of the overtraining syndrome The stress has its roots in the animal’s defense reactions that come to answer to the dangers found in its fatifue.

Different cerebral structures are involved in different defense strategies, depending on the level of the threats perceived by the individual.

Trials with animal models has evidenced that in potentially dangerous situations, the structures involved would be the septo-hippocampal system and the tonsils. These structures receive information gathered by different sensorial systems, thus creating a representation of the outside world. The septo-hippocampal system initially performs the conferee function, comparing the sensorial data synthesis at that moment with those predictions that take into account the memories stored in several spots of the Central Nervous System CNSas well as the action plans generated by the prefrontal cortex.

Whenever there is coherence between both representations, the septo-hippocampal system continues to exert its conferee task. However, whenever it is detected a discrepancy between what is expected and what happened, the septo-hippocampal system starts in generating an inhibition of the behavior, an increasing vigilance level, driving the individual’s attention to possible sources of danger.

When the danger signs are clear but still are far away, the tense immobility reaction is quite common, whose neural substrate is probably the ventral portion of the periaqueductal anx matter PGM of the mesencephalon 13, The PGM seems to be the major structure responsible by the fight and escape schedule that is analogically related to the panic attacks The PGM, together with the hypothalamus schedules the behavior, hormonal and neurovegetative manifestations of the defense neurotransmmitters.

It was also verified that the stimulation of the serotonergic way, which is originated in the medial nucleus of the Raphe, and preferably innervates the septo-hippocampus, determines the behaviorist inhibition that characterizes the defense Seeking to understand the neurophysiology that involves the anxiety and the stress, substances such as noradrenaline, dopamine, serotonin, melatonin, acetylcholine, and choline, glutamine, aspartate, glycine, taurine, histamine, GABA, adenosine, and inosine, cholecystokinin Neyrotransmitters have been studied.

Several of these neurotransmitters are synthesized through precursors delivered by the food, and they are directly influenced by the diet. Therefore, proteins, carbohydrates, and fat, which are the major constituents of the diet, act not only as energetic substrate, but also as precursors of several neuroactive substances.

Brain neurotransmitters in fatigue and overtraining.

According to Prasad 16the use of neurotransmitter precursors as dietetic supplements both in humans and in animals has presented profound effects on the neurochemistry and in the behavior. Presently, it is believed that the serotonin has a double role in the regulation of the defense behavior.

The signs of danger would stimulate the defense system through the tonsils, and at the same time, they would activate the serotoninergic neurons of the dorsal nucleus of the Raphe, neurotranssmitters will innervate both the tonsils and the PGM through different nervous ways. The serotonin would facilitate the active defense reactions in the tonsils, and it would inhibit them in the Neurotransmittees.

Therefore, the serotonin-mediated responses would have an adaptation sense, as for levels of potential or distal danger it is convenient that the fight and escape behaviors are inhibited, making possible for the individual to choose the best strategies that means: Serotonin could even to increase the anxiety, acting on the tonsils in order to restrain the panic, acting on the PGM At least five different serotonin receptors were identified neurotransmitteds the cellular membranes, each of them with a sole molecular structure, pharmacological action, and anatomic distribution into the central nervous system.

These receptors have a fundamental role in the overtraining syndrome. Studies indicate that the sensitivity changes, or low regulation of the central and peripheral serotonin receptors are associated to the fatigue during prolonged exercises 19and aand the body adaptation in the resistance training More recently, a case study performed by Uusitalo et al.

Such deficiency is part of the neurophysiologic basis in ahd depressive mood, and a worsening in the performance, since the serotoninergic activity is particularly involved in the maintenance of the controlling process of the fztigue and in fatiue motor activity.

As the high brqin activity during the stress leads to a high level of usage of the serotonin, the continuing stress can lead to a functional neurotransmitterz in the production of such neurotransmitter, and the deficiency of food originated precursors can decrease its cerebral braln 3. Fatigue can be defined as the set of manifestations produced by the work or prolonged exercises, which has neurotransmiyters consequence a decreasing functional capability in keeping or continuing the expected outcome Several works in the Physiology area defines the term fatigue as “incapacity to maintain the power outcome” both in resistance exercises and in the overtraining states 10,20, Its etiology has brought a overttraining interest, mainly due to its multifactor feature, and it can be divided in two components: That division takes into account interactive metabolic factors affecting the muscles peripheral fatigue and the brain central fatigue upon the accomplishment of an intense physical work in athletes and fatiyue individuals 6.

In resistance sports, the overtraining syndrome is characterized by a overtrakning fatigue and apathy. Some researchers have been studying such fatigue, but its nature is yet to be clearly explained. It can be muscular fatigue, and ofertraining may be related to the depression or even resulting from diseases.


In general, the muscular fatigue involves a lack of ability in generating energy in a sufficient amount o maintain a given physical activity. The specific energetic path responsible by the muscular fatigue depends on the endurance and intensity of the event.

It is possible that the energetic metabolism that is secondary to the endocrine changing is altered in the overtraining syndrome, and consequently brainn the fatigue as well. Several diseases are neurotransmittters to the fatigue, including anemia, mononucleosis, hypoglycemia, hypothyroidism, and the chronic fatigue syndrome Several case reports have demonstrated that the worsening in the sportive performance is associated to persisting viral infections for prolonged periods of time Whatever may be the cause of the fatigue in the overtraining syndrome, it is clear that there are more questions than definitive answers.

The hypothesis that the exercise affects the protein and aminoacid metabolism has been revaluated, and they significantly contribute to the outcome in prolonged exercises The serotonin has an important role in investigating the development of the central fatigue, acting in the formation of the memory, in the neurotranmitters, in the sleep and mood 33in the suppression of the appetiteand in the alterations un the strength perception Those training induced alterations in the metabolism of the nutrients have been proposed as one of the factors that contribute to the overtraining syndrome.

The “Central Fatigue Hypothesis” connects fatigie signs and symptoms of the syndrome to similar symptoms than those that appear whenever there is an increasing concentration in the cerebral neurotransmitter serotonin It has been demonstrated that the cerebral serotonin level depends on the free in the plasma tryptophan that increases whenever the free fatty acid concentration increases.

Due to the increase of the free fatty acid in the plasma levels during the resistance training, this theory proposes that the levels of cerebral serotonin increase before the presence of the overtraining 41, A similar alternative explanation admits that the ramified chain of aminoacids and tryptophan compete each other to reach the brain, and to penetrate into the hematoencephalic barrier.

According to this hypothesis, the decrease in the concentrations of the ramified chain aminoacids raises the level of the free tryptophan in the plasma and of the cerebral serotonin Up to this moment, the studies performed to determine the cerebral level of the tryptophan were made in animals.

Those studies with rats present uniformity Data obtained neirotransmitters those studies support the above outlined hypothesis that the increase in the production of the serotonin in the brain, and its major metabolite 5-HIAA has direct relationship to the accomplishment of prolonged exercises 44,45 and to the appearance of the fatigue signs.

Both theories suggest that the cerebral serotonin increases up to the point that the fatigue and other overtraining syndrome’s symptoms appear. This is not the only neurotransmitter associated to the perception and development of the fatigue, but it is the one that is under study However, the big existing discrepancy between experimental protocols makes it difficulty to analyze the results. Even so, there are concrete evidences of the important role of the serotonin in the performance during prolonged exercises In the medical literature there are several meanings to the overtraining syndrome that generally are associated to the overloaded training, called overreaching.

The overloaded training is related to the hard training for a few days, followed by a short recovery period that in this case is essential.

The physiological homeostasis of the body needs to be stimulated through the intense training in order to imrove the sportive performance capability.

This process is called super-compensation. Several days of intentionally heavy training are followed by a lighter training and resting for a few days, in order to reach the super-compensation and the performance climax.

It is essential that the necessary time to achieve the super-compensation is recognized. If an athlete is not yet adapted before a new stimulus is given, there will be a progressive and higher imbalance The result is the overreaching, that is a set of transitory symptoms, signs and changes that appear during the heavy training, and they are diagnosed through tests.

Both the overreaching and the overtraining syndrome cause a decrease in the performance, as well as similar signs and symptoms, but they have different recovery time. The overreaching needs two or three weeks to re-establish the sportive performance of the athlete, but in the overtraining syndrome, this process takes months or even years 7, The overtraining syndrome affects a considerable percentage of individuals involved in and resting intensive training programs.

It is defined as a neuroendocrine disorder hypothalamohypophysial that results from an imbalance between the demand of the exercise and the functional capability, and it may be aggravated by an inadequate recovery, thus causing a decrease in the sportive and athletic performance, the incidence of bruises, neuroendocrine changes, alterations in the mood, constant fatigue, among other symptoms 8.

Athletes of all performance levels may develop the syndrome, and a relevant number of signs and symptoms have been associated to it. But despite such extended list, up to this moment there are not yet quite established criteria 8maybe due to the lack of a culture implying in a systematic evaluation routine for sportsmen. The malfunction or imbalance in the autonomous nervous system was presented as the reason for the signs and symptoms of the syndrome