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00005768-201008000-0000600005768_2010_42_1469_leite_serotonin_8miscellaneous-article< 97_0_11_5 >Medicine & Science in Sports & Exercise©2010The American College of Sports MedicineVolume 42(8)August 2010pp 1469-1476Central Fatigue Induced by Losartan Involves Brain Serotonin and Dopamine Content[BASIC SCIENCES]LEITE, LAURA H. R.1; RODRIGUES, ALEX G.2; SOARES, DANUSA D.3; MARUBAYASHI, UMEKO1; COIMBRA, CÂNDIDO C.11Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Minas Gerais, BRAZIL; 2Institute of Biological and Health Sciences, Pontifícia Universidade Católica, Minas Gerais, BRAZIL; and 3Department of Physical Education, School of Physical Education, Physical Therapy and Occupational Therapy, Federal University of Minas Gerais, Minas Gerais, BRAZILAddress for correspondence: Cândido C. Coimbra, Ph.D., Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas/UFMG, Av. Antônio Carlos, 6627, 31270-901 Belo Horizonte, Minas Gerais, Brazil; E-mail: for publication September 2009.Accepted for publication December 2009.ABSTRACTPurpose: To investigate the influence of angiotensin II (Ang II) AT1 receptors blockade on central fatigue induced by brain content of serotonin (5-HT) and dopamine (DA) during exercise.Methods: Losartan (Los) was intracerebroventricularly injected in rats before running until fatigue (n = 6 per group). At fatigue, brains were quickly removed for measurement of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), DA, and 3,4-dihydroxyphenylacetic acid by high-pressure liquid chromatography in the preoptic area, hypothalamus, hippocampus, and frontal cortex.Results: Intracerebroventricular injection of Los increased 5-HT content in the preoptic area and hypothalamus. Such results correlated positively with body heating rate and inversely with time to fatigue. On the other hand, time to fatigue was directly correlated with the diminished concentration of 5-HT in the hippocampus of Los rats. Although the levels of DA were not affected by Los treatment during exercise in any of the brain areas studied, a higher 5-HT/DA ratio was seen in the hypothalamus of Los animals. This higher hypothalamic 5-HT/DA ratio correlated positively with body heating rate and negatively with time to fatigue.Conclusions: Our results show that central fatigue due to hyperthermia and increased body heating rate induced by central Ang II AT1 receptor blockade in exercising rats is related with higher 5-HT content in the preoptic area and hypothalamus as well as with decreased levels of this neurotransmitter in the hippocampus. Furthermore, the interaction between 5-HT and DA within the hypothalamus seems to contribute to hyperthermia and premature central fatigue after angiotensinergic inhibition.Central fatigue during prolonged exercise is considered to be affected by accumulation or depletion of neurotransmitters, particularly serotonin (5-HT) (3,10,23,24). High 5-HT activity is associated with lethargy and loss of central drive/motivation (3,23). In fact, evidence suggests that a rise in 5-HT content in major brain areas responsible for thermoregulation, such as the preoptic area/anterior hypothalamus, is related to heat production and precipitation of fatigue (3,5,27,29). Taking into account this last observation, substances that elevate body temperature, such as in the case of fever induced by cytokines, may anticipate central fatigue through elevation of brain 5-HT content (7,8).Although the role of 5-HT on central fatigue has been well documented, it is likely that other neurotransmitters are capable of influencing fatigue, such as dopamine (DA) (3,10,12,23). This monoamine has been suggested to interact with 5-HT during exercise, affecting exercise performance (12,23). DA neurotransmission is associated with many physiological functions that could modify running performance, such as arousal, reward, and motivation (2,12,15,23). Central DA metabolism is enhanced during exercise in animals (2,12,15), and its central elevation has been linked with a delay in fatigue despite higher body temperature at fatigue point and heat storage during exercise (2,12,15).High internal body temperature and increased heat storage have been proposed as limiting factors that reduce the central nervous system's drive for exercise performance, thus protecting the brain from thermal damage (13,28,35). Therefore, considering that serotonergic and dopaminergic interaction is involved with central fatigue, which is coincident with high body temperature and/or heat storage, the activation of mechanisms that could modulate the activity of such systems would improve exercise performance by inducing thermal adjustments.We have recently shown that intracerebroventricular infusion of the widely used antihypertensive drug losartan (Los; Angiotensin II AT1 receptor antagonist) reduces running performance in rats owing to a heat imbalance characterized by higher metabolic cost and reduced peripheral heat loss. These responses resulted in hyperthermia and increased body heating rate that were indirectly related to time to fatigue (19,21). Besides the actions of angiotensin II (Ang II) on thermoregulation and metabolic cost during exercise, it is still not known whether the effect of angiotensinergic blockade on heat storage may be linked to serotonergic and/or dopaminergic pathways that exhibit relevant thermoregulatory and exercise performance effects (2,12,22,29). Therefore, this study aimed at investigating the possible interaction between the central angiotensinergic system and 5-HT and DA content in areas of the central nervous system involved in thermoregulation and motor activity, including the preoptic area, hypothalamus, frontal cortex, and hippocampus, during exercise.METHODSAnimals.Male Wistar rats, 11-12 wk old (290 ± 10 g), were housed individually at a room temperature of 22° ± 2°C, under 14:10-h light-dark cycles, and had free access to water and rat chow. After anesthesia was achieved using a mixture of ketamine (115 mg·kg−1 body weight, intraperitoneally) and xylazine (6 mg·kg−1 body weight intraperitoneally), the rats were fixed to a stereotaxic apparatus (M-900; David Kopf Instruments, Tujunga, CA), and a guide cannula (22 gauge) was implanted into the right lateral cerebral ventricle using a previously described technique (19-21). Also, during this surgical procedure, a TR3000 VM-FH temperature sensor (Mini Mitter, Sun River, OR) was implanted into the peritoneal cavity through a small incision in the linea alba. All animals were allowed to recover for at least 1 wk before being submitted to the experiments. The animals were acclimatized to exercise on the motor-driven treadmill by running at a speed of 15 m·min−1 at 5% inclination for 5 min·d−1 during four consecutive days before the experiments. This preliminary exercise did not constitute training. Its purpose was to teach the animals in which direction to run (19-21). Electrical stimulation was determined according to each animal's tolerability. All experiments were approved by the ethics committee of the Federal University of Minas Gerais for the Care and Use of Laboratory Animals and were carried out in accordance with the regulations described in the committee's guiding principles manual. In addition, the experimental protocol followed the American College of Sports Medicine's animal care standards.Experimental protocol.On the day of the experiment, each animal was allowed to rest for 1 h in the rodent treadmill chamber before being submitted to the test. A needle (30 gauge) protruding 0.3 mm from the tip of the guide cannula was introduced into the right lateral cerebral ventricle. This needle was connected to a Hamilton syringe. One minute before exercise, 2 μL of 0.15 M NaCl (Sal) or 2 μL of Los (Merck Sharpe & Dohme, Campinas, Brazil; 60 nmol) were injected into the right lateral ventricle. The dose of Los was based on the results of our previous experiments (19-21). Rats were randomly assigned to groups receiving either Sal or Los solution (n = 6 each group). The researchers were blinded to the randomization scheme. Immediately after the intracerebroventricular injections, the animals were individually submitted to running exercise until fatigue at constant speed and inclination (18 m·min−1 and 5% inclination). Exercise was performed on a motor-driven treadmill (Modular Treadmill; Columbus Instruments, Columbus, OH) between 10:00 and 14:00 h at a room temperature of 22°C ± 2°C. The intensity of exercise corresponded to an oxygen uptake of ∼66% of maximal oxygen uptake, which represents a physical activity of moderate intensity (2,4,16,20). Body temperature was recorded continuously by telemetry. Fatigue was defined as the point at which the animals were no longer able to keep pace with the treadmill (19-21). Total time to fatigue (min) and workload (kg·m) were considered indexes of exercise performance.As soon as the fatigue point was reached, the animals were killed by decapitation. The brain was quickly removed and washed with ice-cold saline. The preoptic area, hypothalamus, hippocampus, and frontal cortex were rapidly dissected on an ice-cold plate (27,29), frozen immediately in dry ice, and stored at −80°C until 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), DA, and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured by high-pressure liquid chromatography (HPLC). The HPLC system was equipped with a reverse-phase column (Shim Pack CLC-OSD; 25 cm, 5 m; Shimadzu, Kyoto, Japan). The potential was set at 850 mV versus an Ag/AgCl reference electrode. A mobile phase containing 31.4 g of citric acid, 584 mg of NaCl, 800 mL of milliQ water, 140 mg of octylsodium sulfate, 48 mL of acetylnitrile, and 28 mL of tetrahydrofurane (pH 3.0) was filtered and pumped through the system at a flow rate of 1.0 mL·min−1. The brain samples were weighed, and the preoptic areas and hypothalamuses homogenized in 200 μL of perchloric acid (0.1 M), while hippocampuses and frontal cortexes were homogenized in 300 μL of the same solution. The homogenates were then centrifuged at 15,000g for 20 min at 6°C, and the supernatants were filtered through a Millipore membrane (0.22 pore size; 13 mm; Millex, São Paulo, Brazil). Twenty microliters of the supernatant was injected into the HPLC-EC system for analysis (Shimadzu). Quantification of 5-HT, 5-HIAA, DA, and DOPAC was made by comparing the peak area to a standard curve.Calculations.Workload (kgm) was calculated as follows: (body weight (kg)) × (total time to fatigue (min)) × (treadmill speed (m·min−1)) × (sinθ (treadmill inclination)) (19-21).Body heating rate (°C·min−1), i.e., rate of increase in body temperature, was calculated as: Δbody temperature /(running time interval), where Δbody temperature is the change in body temperature (Tf − Ti), Tf = body temperature at fatigue point, and Ti = initial body temperature measured before exercise (21).Heat storage rate (cal·min−1) was calculated as follows: (Δbody temperature) × mc/(total time to fatigue), where m is the body weight (g) and c is the specific heat of the body tissues (0.826 cal·g−1·°C−1) (21).Statistical analysisData are reported as mean ± SEM. A two-way ANOVA was used for determining differences between time and treatment, on one hand, and the interactions between them, on the other. This was done to evaluate the differences in changes of body temperature. Significant interactions observed by ANOVA were further evaluated by Newman-Keuls post hoc analysis to locate significant differences between means. Time to fatigue, workload, body heating rate, heat storage rate, as well as monoamines concentrations were compared using unpaired Student's t-test. The correlations were assessed using Pearson correlation coefficient. Significance level was set at P < 0.05.RESULTSAs previously seen and evidenced in Table 1, intracerebroventricular injection of Los reduced time to fatigue and workload by ∼59% and 58%, respectively, compared with the Sal-treated group (P < 0.01). Although exercise promoted a rapid increase in body temperature in both groups, at fatigue point, the body temperature of Los-treated rats was 0.33°C higher than that of Sal animals (P < 0.01). To compare the total thermal effects of exercise in both experimental groups, body heating rate and heat storage rate were calculated. At fatigue, body heating rate and heat storage rate of Los-treated rats were ∼150% and 97% higher, respectively, in comparison with Sal-treated rats (P < 0.01).TABLE 1. Effect of intracerebroventricular injection of 2 μL of 0.15 M NaCl (Sal) or losartan (Los; 60 nmol) on exercise performance and thermoregulatory parameters during exercise until fatigue.Figure 1 shows 5-HT and 5-HIAA content in the brain areas studied. At fatigue, 5-HT content was significantly higher in the preoptic area (Fig. 1A) and hypothalamus (Fig. 1B) of Los-exercised rats compared with Sal-exercised animals. Such increases of 5-HT were approximately 4 and 34 times higher within the preoptic area and hypothalamus, respectively (P < 0.01). On the other hand, in fatigued Los-exercised rats, a lower content of 5-HT was observed in the hippocampus in comparison with the control group (P < 0.05; Fig. 1C). Within the frontal cortex, 5-HT concentration was not affected by angiotensinergic blockade during exercise (Fig. 1D). As also seen in Figure 1, the levels of 5-HIAA were enhanced by ∼194% and 119% in the preoptic area and hypothalamus, respectively (P < 0.05), but not in the hippocampus and frontal cortex.FIGURE 1-Effect of intracerebroventricular injection of 2 μL of 0.15 M NaCl (Sal) or losartan (Los; 60 nmol) on concentrations of 5-HT and 5-HIAA in the preoptic area (A), hypothalamus (B), hippocampus (C), and frontal cortex (D) after exercise until fatigue. Values are expressed as mean ± SEM, n = 6 each group. *P < 0.05 compared with Sal-treated group.Los treatment during exercise did not interfere with DA concentration in any of the brain areas studied (Fig. 2). However, the concentration of DOPAC in the preoptic area and hypothalamus of Los animals increased by ∼144% and 102%, respectively, in comparison with Sal-treated rats (P < 0.05). No change in the level of DOPAC between the groups was observed in the hippocampus and frontal cortex (Fig. 2).FIGURE 2-Effect of intracerebroventricular injection of 2 μL of 0.15 M NaCl (Sal) or losartan (Los; 60 nmol) on concentrations of DA and DOPAC in the preoptic area (A), hypothalamus (B), hippocampus (C), and frontal cortex (D) after exercise until fatigue. Values are expressed as mean ± SEM, n = 6 each group. *P < 0.05 compared with Sal-treated group.When analyzing the two clusters of data together, i.e., Sal and Los animals, the increased concentration of 5-HT in the preoptic area (r = 0.85, P < 0.01) and hypothalamus (r = 0.75, P < 0.01) of Los rats correlated positively with body heating rate (Figs. 3A and C). Moreover, an inverse relationship between time to fatigue and 5-HT levels in the preoptic area (r = 0.82, P < 0.01) and hypothalamus (r = 0.70, P < 0.01; Figs. 3B and D) was verified. On the contrary, the correlation between 5-HT level in the hippocampus and total time to fatigue (r = 0.56, P < 0.05) was direct (Fig. 3F). However, no correlation between body heating rate and 5-HT content in the hippocampus was found (Fig. 3E). Although no correlation was observed between DA concentration in any area of the brain, and either body heating rate or time to fatigue, the ratio between the content of 5-HT and DA (5-HT/DA) increased significantly in the hypothalamus of Los rats (P < 0.01; Fig. 4A). In addition, the increased 5-HT/DA ratio of the hypothalamus of Los rats correlated positively with body heating rate (r = 0.73, P < 0.01) and negatively with time to fatigue (r = 0.56, P < 0.05; Figs. 4B and C).FIGURE 3-Correlation between 5-HT concentration in preoptic area and body heating rate (A) and time to fatigue (B): correlation between 5-HT concentration in hypothalamus and body heating rate (C) and time to fatigue (D); correlation between 5-HT concentration in hippocampus and body heating rate (E) and time to fatigue (F) in rats treated with 2 μL of 0.15 M NaCl (Sal, open circles) or losartan (Los; 60 nmol; filled circles).FIGURE 4-A, Effect of intracerebroventricular injection of 2 μL of 0.15 M NaCl (Sal) or losartan (Los; 60 nmol) on 5-HT/DA ratio in the preoptic area, hypothalamus, hippocampus, and frontal cortex after exercise until fatigue. Values are expressed as mean ± SEM, n = 6 each group. *P < 0.05 compared with Sal-treated group. Correlation between 5-HT/DA ratio in the hypothalamus and body heating rate (B) and time to fatigue (C) in rats treated with 2 μL of 0.15 M NaCl (Sal, open circles) or losartan (Los; 60 nmol, filled circles).DISCUSSIONThe present study demonstrates that central fatigue due to hyperthermia and increased body heating rate induced by central Ang II AT1 receptors blockade in exercising rats is related with the higher 5-HT content in the preoptic area and hypothalamus as well as with the decreased level of this neurotransmitter in the hippocampus. In addition, the higher hypothalamic 5-HT/DA ratio shown by Los rats, which correlated directly with body heating rate and inversely with time to fatigue, indicates that 5-HT and DA interaction in this region may contribute to hyperthermia and premature central fatigue after angiotensinergic inhibition. Taken together, the data indicate that angiotensinergic transmission has important effects on 5-HT levels in the brain during exercise, whose interaction with DA affects central fatigue probably through modulation of body temperature.We have recently shown that intracerebroventricular infusion of Los precipitates fatigue, through an increase in metabolic cost, and hyperthermia, due to reduced peripheral heat loss and increased heat production during exercise (19,21). Elevated internal body temperature and increased heat storage have been proposed as limiting factors to physical performance (13,28,35). It is important to point out that fatigue is considered a defense mechanism that prevents the development of homeostatic imbalances capable of endangering physical integrity, especially of the brain because of its vulnerability to hyperthermia (18,25). Mechanisms of fatigue include factors of peripheral and central origin, the latter being characterized by modifications within the central nervous system that impairs an adequate drive to the muscles (10,25).Increased brain serotonergic activity contributes to the development of fatigue possibly by causing lethargy and loss of drive (10,23,25). It has been shown that high concentrations of 5-HT in the preoptic area and hypothalamus verified after running exercise are related with exercise-induced hyperthermia and decreased running performance (27,29). Furthermore, although swimming training induces similar hypothalamic 5-TH concentration compared with sedentary rats, after an exhaustive training program with an insufficient recovery period, hypothalamic 5-HT concentration increases (5). Such elevated 5-HT content, akin to the observed in the present study, may contribute to the poor exercise performance during periods of excessive training (5). The present findings give evidence that inhibition of the central angiotensinergic system during dynamic exercise, which resulted in increased 5-HT content in the preoptic area and hypothalamus associated with hyperthermia and higher body heating rate, may have an antiergogenic effect, decreasing time to fatigue to protect the organism against thermal damage. The indirect relation between time to fatigue and the enhanced 5-HT concentration in the preoptic area and hypothalamus of Los rats also supports this observation.We cannot disregard the fact that serotonergic neurons have many other important functions in the central nervous system, including the control of motor activity (3,23,31-33). The hippocampus is also considered to play a role in motor activity control (31-33), as suggested by findings that local infusion of 5-HT in this site produces an increase in the motor activity of rats (31,33) and that lower hippocampal serotonergic activity precipitates fatigue during exercise (27,29). Our data agree with these findings because these show decreased 5-HT concentrations in the hippocampus that correlated directly with time to fatigue but not with body heating rate. The decreased level of 5-HT in the hippocampus may have contributed to the lower exercise performance shown by Los-treated rats through modulation of motor activity. As previously seen, it seems that the hippocampus' involvement with central fatigue is of motor rather than thermal nature (27,29). In addition, such opposite 5-HT turnover in areas of the central nervous system involved in thermoregulation and motor activity after inhibition of the brain angiotensinergic system agrees with findings that the serotonergic system controls its effects through selective alteration of 5-HT concentration according to specific brain regions (6,27,29).It is well defined that DA content is increased during exercise, including within the hypothalamus and hippocampus (2,12,15). Although increased brain DA results in improvement of exercise performance (ergogenic effect), this response is also followed by hyperthermia and enhanced heat storage (2,15). When DA acts on the mesolimbic reward system, safe limits of temperature seem to be exceeded by overruling inhibitory signals from the central nervous system, which could alter perceived effort and compromise exercise performance (2,12,15). In the present study, angiotensinergic blockade during exercise did not alter the concentrations of DA in the brain areas studied. These findings corroborate evidence that intracerebroventricular injection of Ang II does not alter the concentrations of DA in the paraventricular nucleus or anterior hypothalamus (26,30). Nevertheless, there are evidence that brain DA levels are similar to resting levels at fatigue (2,12), which leaves open the possibility that the concentration of DA increased differently among the groups in between exercise.The preoptic area/anterior hypothalamus is the major brain region involved in thermoregulation that integrates thermal inputs with energy-linked metabolic processes (9,11,14,17). This is supported by the fact that this area contains both warm-sensitive and cold-sensitive neurons that respond to small changes in temperature (14,17) and also by the fact that lesion or pharmacologic blockade of the preoptic area/anterior hypothalamus produces a severe impairment in thermoregulation (14,17). In addition to the preoptic area, the hypothalamus also has influence on body temperature control. Lin et al. (22) demonstrated that elevation of 5-HT levels in the hypothalamus through the infusion of 5-hydroxytryptophan resulted in hyperthermic effects, which were brought forth by increased metabolic heat production and decreased heat loss. Similarly, it has also been shown that exercise increases DA concentration not only in the hypothalamus but also in the preoptic area, associated with elevated body temperature (2,15). Therefore, it seems reasonable to suggest that Los is hypothetically perfused to these regions after being injected into the cerebral ventricle, altering 5-HT and DA release and, consequently, thermal control. However, the mechanisms involved in these hyperthermia-induced effects, as well as how brain neurotransmission affects thermoregulation during exercise, still require clarification.The synthesis and turnover of 5-HT in the central nervous system depend on changes in the availability of brain tryptophan, the enzyme responsible for catalyzing the first reaction in the synthesis of 5-HT (3,10). It is known that the exercise-induced increase in plasma free fatty acids indirectly facilitates the entry of tryptophan into the brain because they compete for the same carrier (albumin) (3,10). In other words, an increase in the concentration of plasma free fatty acid elevates the free tryptophan level. We have recently shown that central angiotensinergic blockade also shifts energy balance during graded exercise in rats fed ad libitum. Such treatment results in a higher and premature increase in plasma free fatty acids already at a low absolute intensity of exercise (20). The association of this last result with the current one indicates that the increased 5-HT content within the preoptic area and hypothalamus induced by Ang II blockade probably benefits from the higher free fatty acids mobilization from adipose tissue.The precursor of DA, tyrosine, also competes with other amino acids, including tryptophan (12), for entry into the brain. This indicates that the interaction between 5-HT and DA may be an important factor affecting the central component of fatigue (12,23). Actually, the "central fatigue hypothesis" postulates that a high 5-HT/DA ratio is associated with poor exercise performance (12,23). This is the case because the increase in 5-HT activity during physical activity contributes to fatigue through inhibition of the dopaminergic system (12,23). To support such an assumption, it has been demonstrated that administration of a 5-HT agonist blocked the exercise-induced increase in DA and that treatment with its antagonist prevented the decrease in DA at exhaustion (1,12). Therefore, the worsening in exercise performance seems to depend mainly on a 5-HT level increase that could superimpose the ergogenic effect of DA. Such a combination of effects was induced by a central angiotensinergic blockade within the preoptic area and hypothalamus at fatigue, leading to a higher hypothalamic 5-HT/DA ratio. Yet, we cannot exclude the possibility that Ang II alters 5-HT and DA metabolism in various brain regions through other factors.In summary, our results provide evidence that central AT1 receptor blockade promotes an increase in the content of 5-HT in the preoptic area and hypothalamus that is related with increased heat production and reduced exercise performance. The decrease in 5-HT levels in the hippocampus associated with the reduced time to fatigue of Los-exercised rats suggests that 5-HT acting in this brain area plays a role in motor activity control during exercise. Furthermore, the interaction between 5-HT and DA within the hypothalamus of Los rats favors hyperthermia and premature central fatigue after angiotensinergic inhibition. Given that losartan is widely prescribed to patients with high blood pressure, kidney disease, and heart failure (34), this study brings further evidence of effects of this drug during exercise. In conclusion, our data indicate that angiotensinergic transmission prevents central fatigue by altering brain 5-HT and DA metabolism during exercise, affecting the control of heat production and exercise capacity.This study was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, and Fundação de Amparo à Pesquisa do Estado de Minas Gerais.The authors have no conflicts to disclose.The technical assistance of André Luis Pimenta de Faria, Janine Costa Ivo, and Patrícia Andrade Guimarães Mitre is greatly appreciated. We thank Maya Mitre for revising the English translation of the manuscript.The results of the present study do not constitute endorsement by the American College of Sports Medicine.REFERENCES1. 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(6):3006-12. 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R.; RODRIGUES, ALEX G.; SOARES, DANUSA D.; MARUBAYASHI, UMEKO; COIMBRA, CÂNDIDO C.Basic Sciences842