Sports Medicine

, Volume 36, Issue 10, pp 881–909 | Cite as

Central Fatigue

The Serotonin Hypothesis and Beyond
  • Romain MeeusenEmail author
  • Philip Watson
  • Hiroshi Hasegawa
  • Bart Roelands
  • Maria F. Piacentini
Review Article


The original central fatigue hypothesis suggested that an exercise-induced increase in extracellular serotonin concentrations in several brain regions contributed to the development of fatigue during prolonged exercise. Serotonin has been linked to fatigue because of its well known effects on sleep, lethargy and drowsiness and loss of motivation. Several nutritional and pharmacological studies have attempted to manipulate central serotonergic activity during exercise, but this work has yet to provide robust evidence for a significant role of serotonin in the fatigue process. However, it is important to note that brain function is not determined by a single neurotransmitter system and the interaction between brain serotonin and dopamine during prolonged exercise has also been explored as having a regulative role in the development of fatigue. This revised central fatigue hypothesis suggests that an increase in central ratio of serotonin to dopamine is associated with feelings of tiredness and lethargy, accelerating the onset of fatigue, whereas a low ratio favours improved performance through the maintenance of motivation and arousal. Convincing evidence for a role of dopamine in the development of fatigue comes from work investigating the physiological responses to amphetamine use, but other strategies to manipulate central catecholamines have yet to influence exercise capacity during exercise in temperate conditions. Recent findings have, however, provided support for a significant role of dopamine and noradrenaline (norepinephrine) in performance during exercise in the heat. As serotonergic and catecholaminergic projections innervate areas of the hypothalamus, the thermoregulatory centre, a change in the activity of these neurons may be expected to contribute to the control of body temperature whilst at rest and during exercise. Fatigue during prolonged exercise clearly is influenced by a complex interaction between peripheral and central factors.


Exercise Capacity Core Temperature Prolonged Exercise Central Fatigue Serotonergic Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Meeusen R, Piacentini MF. Exercise, fatigue, neurotransmission and the influence of the neuroendocrine axis. Adv Exp Med Biol 2003; 527: 521–5PubMedCrossRefGoogle Scholar
  2. 2.
    Nybo L, Secher NH. Cerebral perturbations provoked by prolonged exercise. Prog Neurobiol 2004; 72 (4): 223–61PubMedCrossRefGoogle Scholar
  3. 3.
    Mosso A. Fatigue. London: Swan Sonnenschein, 1904Google Scholar
  4. 4.
    Romanowski W, Grabiec S. The role of serotonin in the mechanism of central fatigue. Acta Physiol Pol 1974; 25 (2): 127–34PubMedGoogle Scholar
  5. 5.
    Chaouloff F, Laude D, Merino D, et al. 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 (8): 1099–106PubMedCrossRefGoogle Scholar
  6. 6.
    Heyes MP, Garnett ES, Coates G. Central dopaminergic activity influences rats ability to exercise. Life Sci 1985; 36 (7): 671–7PubMedCrossRefGoogle Scholar
  7. 7.
    Acworth I, Nicholass J, Morgan B, et al. Effect of sustained exercise on concentrations of plasma aromatic and branched-chain amino acids and brain amines. Biochem Biophys Res Commun 1986; 137 (1): 149–53PubMedCrossRefGoogle Scholar
  8. 8.
    Newsholme EA, Acworth I, Blomstrand E. Amino acids, brain neurotransmitters and a function link between muscle and brain that is important in sustained exercise. In: Benzi G, editor. Advances in myochemistry. London: John Libbey Eurotext, 1987: 127–33Google Scholar
  9. 9.
    Edwards RH. Human muscle function and fatigue. Ciba Found Symp 1981; 82: 1–18PubMedGoogle Scholar
  10. 10.
    Bigland-Ritchie B, Woods JJ. Changes in muscle contractile properties and neural control during human muscular fatigue. Muscle Nerve 1984; 7 (9): 691–9PubMedCrossRefGoogle Scholar
  11. 11.
    Booth FW, Thomason DB. Molecular and cellular adaptation of muscle in response to exercise: perspectives of various models. Physiol Rev 1991; 71 (2): 541–85PubMedGoogle Scholar
  12. 12.
    Bergstrom J, Hermansen L, Hultman E, et al. Diet, muscle glycogen and physical performance. Acta Physiol Scand 1967; 71 (2): 140–50PubMedCrossRefGoogle Scholar
  13. 13.
    Sawka MN, Young AJ, Latzka WA, et al. Human tolerance to heat strain during exercise: influence of hydration. J Appl Physiol 1992; 73 (1): 368–75PubMedGoogle Scholar
  14. 14.
    Cooper JR, Bloom FE, Roth RH. The biochemical basis of neuropharmacology. 8th ed. New York: Oxford University Press, 2003Google Scholar
  15. 15.
    Fernstrom JD. Role of precursor availability in control of monoamine biosynthesis in brain. Physiol Rev 1983; 63 (2): 484–546PubMedGoogle Scholar
  16. 16.
    Fernstrom JD, Wurtman RJ. Brain serotonin content: increase following ingestion of carbohydrate diet. Science 1971; 174 (13): 1023–5PubMedCrossRefGoogle Scholar
  17. 17.
    Fernstrom JD, Hirsch MJ, Faller DV. Tryptophan concentrations in rat brain: failure to correlate with free serum tryptophan or its ratio to the sum of other serum neutral amino acids. Biochem J 1976; 160 (3): 589–95PubMedGoogle Scholar
  18. 18.
    Pardridge WM. Tryptophan transport through the blood-brain barrier: in vivo measurement of free and albumin-bound amino acid. Life Sci 1979; 25 (17): 1519–28PubMedCrossRefGoogle Scholar
  19. 19.
    Chaouloff F, Kennett GA, Serrurrier B, et al. Amino acid analysis demonstrates that increased plasma free tryptophan causes the increase of brain tryptophan during exercise in the rat. J Neurochem 1986; 46 (5): 1647–50PubMedCrossRefGoogle Scholar
  20. 20.
    Ide K, Secher NH. Cerebral blood flow and metabolism during exercise. Prog Neurobiol 2000; 61 (4): 397–414PubMedCrossRefGoogle Scholar
  21. 21.
    Issekutz B, Bortz WM, Miller HI, et al. Turnover rate of plasma FFA in humans and in dogs. Metabolism 1967; 16 (11): 1001–9PubMedCrossRefGoogle Scholar
  22. 22.
    Spriet LL. Regulation of skeletal muscle fat oxidation during exercise in humans. Med Sci Sports Exerc 2002; 34 (9): 1477–84PubMedCrossRefGoogle Scholar
  23. 23.
    Havel RJ, Pernow B, Jones NL. Uptake and release of free fatty acids and other metabolites in the legs of exercising men. J Appl Physiol 1967; 23 (1): 90–9PubMedGoogle Scholar
  24. 24.
    Curzon G, Friedel J, Katamaneni BD, et al. Unesterified fatty acids and the binding of tryptophan in human plasma. Clin Sci Mol Med 1974; 47: 415–24PubMedGoogle Scholar
  25. 25.
    Pardridge WM. Brain metabolism: a perspective from the blood-brain barrier. Physiol Rev 1983; 63 (4): 1481–535PubMedGoogle Scholar
  26. 26.
    Blomstrand E, Celsing F, Newsholme EA. Changes in plasma concentrations of aromatic and branched-chain amino acids during sustained exercise in man and their possible role in fatigue. Acta Physiol Scand 1988; 133 (1): 115–21PubMedCrossRefGoogle Scholar
  27. 27.
    van Hall G, Raaymakers JS, Saris WH, et al. Ingestion of branched-chain amino acids and tryptophan during sustained exercise in man: failure to affect performance. J Physiol 1995; 486 (Pt 3): 789–94PubMedGoogle Scholar
  28. 28.
    MacLean DA, Graham TE, Saltin B. Branched-chain amino acids augment ammonia metabolism while attenuating protein breakdown during exercise. Am J Physiol 1994; 267 (6 Pt 1): E1010–22PubMedGoogle Scholar
  29. 29.
    Bequet F, Gomez-Merino D, Berthelot M, et al. vidence that brain glucose availability influences exercise-enhanced extracellular 5-HT level in hippocampus: a microdialysis study in exercising rats. Acta Physiol Scand 2002; 176 (1): 65–9PubMedCrossRefGoogle Scholar
  30. 30.
    Artigas F, Romero L, de Montigny C, et al. Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci 1996; 19 (9): 378–83PubMedCrossRefGoogle Scholar
  31. 31.
    Davis JM, Bailey SP. Possible mechanisms of central nervous system fatigue during exercise. Med Sci Sports Exerc 1997; 29 (1): 5–57Google Scholar
  32. 32.
    Bailey SP, Davis JM, Ahlborn EN. Serotonergic agonists and antagonists affect endurance performance in the rat. Int J Sports Med 1993; 14 (6): 330–3PubMedCrossRefGoogle Scholar
  33. 33.
    Gerald MC. Effects of (+)-amphetamine on the treadmill endurance performance of rats. Neuropharmacology 1978; 17 (9): 703–4PubMedCrossRefGoogle Scholar
  34. 34.
    Burgess ML, Davis JM, Borg TK, et al. Intracranial self-stimulation motivates treadmill running in rats. J Appl Physiol 1991; 71 (4): 1593–7PubMedGoogle Scholar
  35. 35.
    Freed CR, Yamamoto BK. Regional brain dopamine metabo lism: a marker for the speed, direction, and posture of moving animals. Science 1985; 229 (4708): 62–5PubMedCrossRefGoogle Scholar
  36. 36.
    Cooper BR, Wang CM, Cox RF, et al. Evidence that the acute behavioral and electrophysiological effects of bupropion (Wellbutrin) are mediated by a noradrenergic mechanism. Neuropsychopharmacology 1994; 11 (2): 133–41PubMedGoogle Scholar
  37. 37.
    Meeusen R, De Meirleir K. Exercise and brain neurotransmission. Sports Med 1995; 20 (3): 160–88PubMedCrossRefGoogle Scholar
  38. 38.
    Gandevia SC. Spinal and supraspinal factors in human muscle fatigue. Physiol Rev 2001; 81 (4): 1725–89PubMedGoogle Scholar
  39. 39.
    Segura R, Ventura JL. Effect of L-tryptophan supplementation on exercise performance. Int J Sports Med 1988; 9 (5): 301–5PubMedCrossRefGoogle Scholar
  40. 40.
    Blomstrand E, Hassmen P, Ekblom B, et al. Administration of branched-chain amino acids during sustained exercise-effects on performance and on plasma concentration of some amino acids. Eur J Appl Physiol Occup Physiol 1991; 63 (2): 83–8PubMedCrossRefGoogle Scholar
  41. 41.
    Stensrud T, Ingjer F, Holm H, et al. L-tryptophan supplementation does not improve running performance. Int J Sports Med 1992; 13 (6): 481–5PubMedCrossRefGoogle Scholar
  42. 42.
    Wilson WM, Maughan RJ. Evidence for a possible role of 5-hydroxytryptamine in the genesis of fatigue in man: administration of paroxetine, a 5-HT re-uptake inhibitor, reduces the capacity to perform prolonged exercise. Exp Physiol 1992; 77 (6): 921–4PubMedGoogle Scholar
  43. 43.
    Davis JM, Bailey SP, Woods JA, et al. Effects of carbohydrate feedings on plasma free tryptophan and branched-chain amino acids during prolonged cycling. Eur J Appl Physiol Occup Physiol 1992; 65 (6): 513–9PubMedCrossRefGoogle Scholar
  44. 44.
    Davis JM, Bailey SP, Jackson DA, et al. Effects of a serotonin (5-HT) agonist during prolonged exercise to fatigue in humans. Med Sci Sports Exerc 1993; 25: S78Google Scholar
  45. 45.
    Hassmen P, Blomstrand E, Ekblom B, et al. Branched-chain amino acid supplementation during 30-km competitive run: mood and cognitive performance. Nutrition 1994; 10 (5): 405–10PubMedGoogle Scholar
  46. 46.
    Varnier M, Sarto P, Martines D, 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 (1): 26–31PubMedCrossRefGoogle Scholar
  47. 47.
    Pannier JL, Bouckaert JJ, Lefebvre RA. The antiserotonin agent pizotifen does not increase endurance performance in humans. Eur J Appl Physiol Occup Physiol 1995; 72 (1-2): 175–8PubMedCrossRefGoogle Scholar
  48. 48.
    Blomstrand E, Andersson S, Hassmen P, et al. Effect of branched-chain amino acid and carbohydrate supplementation on the exercise-induced change in plasma and muscle concentration of amino acids in human subjects. Acta Physiol Scand 1995; 153 (2): 87–96PubMedCrossRefGoogle Scholar
  49. 49.
    Alves MN, Ferrari-Auarek WM, Pinto KM, et al. Effects of caffeine and tryptophan on rectal temperature, metabolism, total exercise time, rate of perceived exertion and heart rate. Braz J Med Biol Res 1995; 28 (6): 705–9PubMedGoogle Scholar
  50. 50.
    Madsen K, MacLean DA, Kiens B, et al. Effects of glucose, glucose plus branched-chain amino acids, or placebo on bike performance over 100 km. J Appl Physiol 1996; 81 (6): 2644–50PubMedGoogle Scholar
  51. 51.
    Marvin G, Sharma A, Aston W, et al. The effects of buspirone on perceived exertion and time to fatigue in man. Exp Physiol 1997; 82 (6): 1057–60PubMedGoogle Scholar
  52. 52.
    Meeusen R, Roeykens J, Magnus L, et al. Endurance performance in humans: the effect of a dopamine precursor or a specific serotonin (5-HT2A/2C) antagonist. Int J Sports Med 1997; 18 (8): 571–7PubMedCrossRefGoogle Scholar
  53. 53.
    Blomstrand E, Hassmen P, Ek S, et al. Influence of ingesting a solution of branched-chain amino acids on perceived exertion during exercise. Acta Physiol Scand 1997; 159 (1): 41–9PubMedCrossRefGoogle Scholar
  54. 54.
    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 (1): 83–91PubMedCrossRefGoogle Scholar
  55. 55.
    Davis JM, Welsh RS, De Volve KL, et al. Effects of branched-chain amino acids and carbohydrate on fatigue during intermittent, high-intensity running. Int J Sports Med 1999; 20 (5): 309–14PubMedCrossRefGoogle Scholar
  56. 56.
    Struder HK, Hollmann W, Platen P, et al. Influence of paroxetine, branched-chain amino acids and tyrosine on neuroendocrine system responses and fatigue in humans. Horm Metab Res 1998; 30 (4): 188–94PubMedCrossRefGoogle Scholar
  57. 57.
    Meeusen R, Piacentini MF, Van Den Eynde S, et al. Exercise performance is not influenced by a 5-HT reuptake inhibitor. Int J Sports Med 2001; 22 (5): 329–36PubMedCrossRefGoogle Scholar
  58. 58.
    Parise G, Bosman MJ, Boecker DR, et al. Selective serotonin reuptake inhibitors: their effect on high-intensity exercise performance. Arch Phys Med Rehabil 2001; 82 (7): 867–71PubMedCrossRefGoogle Scholar
  59. 59.
    Piacentini MF, Meeusen R, Buyse L, et al. No effect of a selective serotonergic/noradrenergic reuptake inhibit or on endurance performance. Eur J Sport Sci 2002; 2 (6): 1–10CrossRefGoogle Scholar
  60. 60.
    Piacentini MF, Meeusen R, Buyse L, et al. No effect of a noradrenergic reuptake inhibitor on performance in trained cyclists. Med Sci Sports Exerc 2002; 34 (7): 1189–93PubMedCrossRefGoogle Scholar
  61. 61.
    Sgherza AL, Axen K, Fain R, et al. Effect of naloxone on perceived exertion and exercise capacity during maximal cycle ergometry. J Appl Physiol 2002; 93 (6): 2023–8PubMedGoogle Scholar
  62. 62.
    Piacentini MF, Meeusen R, Buyse L, et al. Hormonal responses during prolonged exercise are influenced by a selective DA/NA reuptake inhibitor. Br J Sports Med 2004; 38 (2): 129–33PubMedCrossRefGoogle Scholar
  63. 63.
    Bridge MW, Weller AS, Rayson M, et al. Responses to exercise in the heat related to measures of hypothalamic serotonergic and dopaminergic function. Eur J Appl Physiol 2003; 89 (5): 451–9PubMedCrossRefGoogle Scholar
  64. 64.
    Nybo L. CNS fatigue and prolonged exercise: effect of glucose supplementation. Med Sci Sports Exerc 2003; 35 (4): 589–94PubMedCrossRefGoogle Scholar
  65. 65.
    Jacobs I, Bell DG. Effects of acute modafinil ingestion on exercise time to exhaustion. Med Sci Sports Exerc 2004; 36 (6): 1078–82PubMedCrossRefGoogle Scholar
  66. 66.
    Strachan A, Leiper J, Maughan R. The failure of acute paroxetine administration to influence human exercise capacity, RPE or hormone responses during prolonged exercise in a warm environment. Exp Physiol 2004; 89 (6): 657–64PubMedCrossRefGoogle Scholar
  67. 67.
    Cheuvront SN, Carter R, Kolka MA, et al. Branched-chain amino acid supplementation and human performance when hypohydrated in the heat. J Appl Physiol 2004; 97 (4): 1275–82PubMedCrossRefGoogle Scholar
  68. 68.
    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: 306–14PubMedCrossRefGoogle Scholar
  69. 69.
    Strachan AT, Leiper JB Maughan RJ.Serotonin2 Ceceptor blockade and thermoregulation during exercise in the heat.Med Sci Sports Exerc 2005;37(3):389–94PubMedCrossRefGoogle Scholar
  70. 70.
    Winnick JJ, Davis JM, Welsh RS, et al. Carbohydrate feedings during team sport exercise preserve physical and CNS function. Med Sci Sports Exerc 2005; 37 (2): 306–15PubMedCrossRefGoogle Scholar
  71. 71.
    Watson P, Hasegawa H, Roelands B, et al. Acute dopamine/noradrenaline reuptake inhibition enhances human exercise performance in warm, but not temperate conditions. J Physiol 2005; 565 (Pt 3): 873–83PubMedCrossRefGoogle Scholar
  72. 72.
    Blomstrand E, Moller K, Secher NH, et al. Effect of carbohydrate ingestion on brain exchange of amino acids during sustained exercise in human subjects. Acta Physiol Scand 2005; 185 (3): 203–9PubMedCrossRefGoogle Scholar
  73. 73.
    Jacobs BL, Eubanks EE. A comparison of the locomotor effects of 5-hydroxytryptamine and 5-hydroxytryptophan administered via two systemic routes. Pharmacol Biochem Behav 1974; 2 (1): 137–9PubMedCrossRefGoogle Scholar
  74. 74.
    Francesconi R, Mager M. Hypothermia induced by chlorpromazine or L-tryptophan: effects on treadmill performance in the heat. J Appl Physiol 1979; 47 (4): 813–7PubMedGoogle Scholar
  75. 75.
    Chaouloff F. Physical exercise and brain monoamines: a review. Acta Physiol Scand 1989; 137 (1): 1–13PubMedCrossRefGoogle Scholar
  76. 76.
    Hillegaart V, Wadenberg ML, Ahlenius S. Effects of 8-OH-DPAT on motor activity in the rat. Pharmacol Biochem Behav 1989; 32 (3): 797–800PubMedCrossRefGoogle Scholar
  77. 77.
    Wilckens T, Schweiger U, Pirke KM. Activation of alpha 2-adrenoceptors suppresses excessive wheel running in the semistarvation-induced hyperactive rat. Pharmacol Biochem Behav 1992; 43 (3): 733–8PubMedCrossRefGoogle Scholar
  78. 78.
    Bailey SP, Davis JM, Ahlborn EN. Effect of increased brain serotonergic activity on endurance performance in the rat. Acta Physiol Scand 1992; 145 (1): 75–6PubMedCrossRefGoogle Scholar
  79. 79.
    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): 3006–12PubMedGoogle Scholar
  80. 80.
    Verger P, Aymard P, Cynobert L, et al. Effects of administration of branched-chain amino acids vs. glucose during acute exercise in the rat. Physiol Behav 1994; 55 (3): 523–6PubMedCrossRefGoogle Scholar
  81. 81.
    Meeusen R, Thorre K, Chaouloff F, et al. Effects of tryptophan and/or acute running on extracellular 5-HT and 5-HIAA levels in the hippocampus of food-deprived rats. Brain Res 1996; 740 (1-2): 245–52PubMedCrossRefGoogle Scholar
  82. 82.
    Calders P, Pannier JL, Matthys DM, et al. Pre-exercise branched-chain amino acid administration increases endurance performance in rats. Med Sci Sports Exerc 1997; 29 (9): 1182–6PubMedCrossRefGoogle Scholar
  83. 83.
    Farris JW, Hinchcliff KW, McKeever KH, et al. Effect of tryptophan and of glucose on exercise capacity of horses. J Appl Physiol 1998; 85 (3): 807–16PubMedGoogle Scholar
  84. 84.
    Calders P, Matthys D, Derave W, et al. Effect of branched-chain amino acids (BCAA), glucose, and glucose plus BCAA on endurance performance in rats. Med Sci Sports Exerc 1999; 31 (4): 583–7PubMedCrossRefGoogle Scholar
  85. 85.
    Connor TJ, Kelliher P, Harkin A, et al. Reboxetine attenuates forced swim test-induced behavioural and neurochemical alterations in the rat. Eur J Pharmacol 1999; 379 (2-3): 125–33PubMedCrossRefGoogle Scholar
  86. 86.
    Gomez-Merino D, Bequet F, Berthelot M, et al. Evidence that the branched-chain amino acid L-valine prevents exercise induced release of 5-HT in rat hippocampus. Int J Sports Med 2001; 22 (5): 317–22PubMedCrossRefGoogle Scholar
  87. 87.
    Kalinski MI, Dluzen DE, Stadulis R. Methamphetamine produc es subsequent reductions in running time to exhaustion in mice. Brain Res 2001; 921 (1-2): 160–4PubMedCrossRefGoogle Scholar
  88. 88.
    Smriga M, Kameishi M, Tanaka T, et al. Preference for a solution of branched-chain amino acids plus glutamine and arginine correlates with free running activity in rats: involvement of serotonergic-dependent processes of lateral hypothalamus. Nutr Neurosci 2002; 5 (3): 189–99PubMedCrossRefGoogle Scholar
  89. 89.
    Rodrigues AG, Lima NR, Coimbra CC, et al. Intracerebroventricular physostigmine facilitates heat loss mechanisms in running rats. J Appl Physiol 2004; 97 (1): 333–8PubMedCrossRefGoogle Scholar
  90. 90.
    Soares DD, Lima NR, Coimbra CC, et al. Evidence that tryptophan reduces mechanical efficiency and running performance in rats. Pharmacol Biochem Behav 2003; 74 (2): 357–62PubMedCrossRefGoogle Scholar
  91. 91.
    Hasegawa H, Ishiwata T, Saito T, et al. Inhibition of the preoptic area and anterior hypothalamus by tetrodotoxin alters thermoregulatory functions in exercising rats. J Appl Physiol 2005; 98 (4): 1458–62PubMedCrossRefGoogle Scholar
  92. 92.
    Blomstrand E, Hassmen P, Newsholme EA. Effect of branched-chain amino acid supplementation on mental performance. Acta Physiol Scand 1991; 143 (2): 225–6PubMedCrossRefGoogle Scholar
  93. 93.
    Curzon G, Knott PJ. Effects on plasma and brain tryptophan in the rat of drugs and hormones that influence the concentration of unesterified fatty acid in the plasma. Br J Pharmacol 1974; 50 (2): 197–204PubMedCrossRefGoogle Scholar
  94. 94.
    Nybo L, Nielsen B, Blomstrand E, et al. Neurohumoral responses during prolonged exercise in humans. J Appl Physiol 2003; 95 (3): 1125–31PubMedGoogle Scholar
  95. 95.
    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 (7): 482–97PubMedCrossRefGoogle Scholar
  96. 96.
    Loubinoux I, Pariente J, Rascol O, et al. Selective serotonin reuptake inhibitor paroxetine modulates motor behavior through practice. A double-blind, placebo-controlled, multidose study in healthy subjects. Neuropsychologia 2002; 40 (11): 1815–21Google Scholar
  97. 97.
    Piacentini MF, Clinckers R, Meeusen R, et al. Effect of bupropion on hippocampal neurotransmitters and on peripheral hormonal concentrations in the rat. J Appl Physiol 2003; 95 (2): 652–6PubMedGoogle Scholar
  98. 98.
    Piacentini MF, Clinckers R, Meeusen R, et al. Effects of venlafaxine on extracellular 5-HT, dopamine and noradrenaline in the hippocampus and on peripheral hormone concentrations in the rat in vivo. Life Sci 2003; 73 (19): 2433–42PubMedCrossRefGoogle Scholar
  99. 99.
    Borg G, Edstrom CG, Linderholm H, et al. Changes in physical performance induced by amphetamine and amobarbital. Psychopharmacologia 1972; 26 (1): 10–8PubMedCrossRefGoogle Scholar
  100. 100.
    Chandler JV, Blair SN. The effect of amphetamines on selected physiological components related to athletic success. Med Sci Sports Exerc 1980; 12 (1): 65–9PubMedGoogle Scholar
  101. 101.
    Burgess ML, Davis JM, Wilson SP, et al. Effects of intracranial self-stimulation on selected physiological variables in rats. Am J Physiol 1993; 264 (1 Pt 2): R149–55PubMedGoogle Scholar
  102. 102.
    Chrapusta SJ, Wyatt RJ, Masserano JM. Effects of single and repeated footshock on dopamine release and metabolism in the brains of Fischer rats. J Neurochem 1997; 68 (5): 2024–31PubMedCrossRefGoogle Scholar
  103. 103.
    Wang GJ, Volkow ND, Fowler JS, et al. PET studies of the effects of aerobic exercise on human striatal dopamine release. J Nucl Med 2000; 41 (8): 1352–6PubMedGoogle Scholar
  104. 104.
    Checkley SA. Neuroendocrine tests of monoamine function in man: a review of basic theory and its application to the study of depressive illness. Psychol Med 1980; 10 (1): 35–53PubMedCrossRefGoogle Scholar
  105. 105.
    Van de Kar LD. 5-HT receptors involved in the regulation of hormone secretion. In: Baumgarten HG, Gothert M, editors. Serotonergic neurons and 5-HT receptors in the CNS. New York: Springer; 1997: 557–62Google Scholar
  106. 106.
    Dinan TG. Serotonin and the regulation of hypothalamic-pituitary-adrenal axis function. Life Sci 1996; 58 (20): 1683–94PubMedCrossRefGoogle Scholar
  107. 107.
    Freeman ME, Kanyicska B, Lerant A, et al. Prolactin: structure, function, and regulation of secretion. Physiol Rev 2000; 80 (4): 1523–631PubMedGoogle Scholar
  108. 108.
    Carli G, Bonifazi M, Lodi L, et al. Changes in the exercise-induced hormone response to branched chain amino acid administration. Eur J Appl Physiol Occup Physiol 1992; 64 (3): 272–7PubMedCrossRefGoogle Scholar
  109. 109.
    Gijsman HJ, Scarna A, Harmer CJ, et al. A dose-finding study on the effects of branch chain amino acids on surrogate markers of brain dopamine function. Psychopharmacology (Berl) 2002; 160 (2): 192–7CrossRefGoogle Scholar
  110. 110.
    De Meirleir K, L’Hermite-Baleriaux M, L’Hermite M, et al. Evidence for serotoninergic control of exercise-induced prolactin secretion. Horm Metab Res 1985; 17 (7): 380–1PubMedCrossRefGoogle Scholar
  111. 111.
    Fischer HG, Hollmann W, De Meirleir K. Exercise changes in plasma tryptophan fractions and relationship with prolactin. Int J Sports Med 1991; 12 (5): 487–9PubMedCrossRefGoogle Scholar
  112. 112.
    Radomski MW, Cross M, Buguet A. Exercise-induced hyperthermia and hormonal responses to exercise. Can J Physiol Pharmacol 1998; 76 (5): 547–52PubMedCrossRefGoogle Scholar
  113. 113.
    Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther 2000; 85 (1): 11–28PubMedCrossRefGoogle Scholar
  114. 114.
    Abdelmalki A, Merino D, Bonneau D, et al. Administration of a GABAB agonist baclofen before running to exhaustion in the rat: effects on performance and on some indicators of fatigue. Int J Sports Med 1997; 18 (2): 75–8PubMedCrossRefGoogle Scholar
  115. 115.
    Conlay LA, Sabounjian LA, Wurtman RJ. Exercise and neuromodulators: choline and acetylcholine in marathon runners. Int J Sports Med 1992; 13 Suppl. 1: S141–2PubMedCrossRefGoogle Scholar
  116. 116.
    Davis JM, Zhao Z, Stock HS, et al. Central nervous system effects of caffeine and adenosine on fatigue. Am J Physiol Regul Integr Comp Physiol 2003; 284 (2): R399–404PubMedGoogle Scholar
  117. 117.
    Guezennec CY, Abdelmalki A, Serrurier B, et al. Effects of prolonged exercise on brain ammonia and amino acids. Int J Sports Med 1998; 19 (5): 323–7PubMedCrossRefGoogle Scholar
  118. 118.
    Banister EW, Cameron BJ. Exercise-induced hyperammonemia: peripheral and central effects. Int J Sports Med 1990; 11 Suppl. 2: S129–42PubMedCrossRefGoogle Scholar
  119. 119.
    Nybo L, Dalsgaard MK, Steensberg A, et al. Cerebral ammonia uptake and accumulation during prolonged exercise in humans. J Physiol 2005; 563 (Pt 1): 285–90PubMedGoogle Scholar
  120. 120.
    Czarnowski D, Langfort J, Pilis W, et al. Effect of a low-carbohydrate diet on plasma and sweat ammonia concentrations during prolonged nonexhausting exercise. Eur J Appl Physiol Occup Physiol 1995; 70 (1): 70–4PubMedCrossRefGoogle Scholar
  121. 121.
    Wagenmakers AJ, Beckers EJ, Brouns F, et al. Carbohydrate supplementation, glycogen depletion, and amino acid metabolism during exercise. Am J Physiol 1991; 260 (6 Pt 1): E883–90PubMedGoogle Scholar
  122. 122.
    Febbraio MA, Snow RJ, Stathis CG, et al. Effect of heat stress on muscle energy metabolism during exercise. J Appl Physiol 1994; 77 (6): 2827–31PubMedGoogle Scholar
  123. 123.
    Marino FE, Mbambo Z, Kortekaas E, et al. Influence of ambient temperature on plasma ammonia and lactate accumulation during prolonged submaximal exercise factor: is IL-6 a candidate? J Muscle Res Cell Motiland self-paced running. Eur J Appl Physiol 2001; 86 (1): 71–8Google Scholar
  124. 124.
    Felipo V, Butterworth RF. Neurobiology of ammonia. Prog Neurobiol 2002; 67 (4): 259–79PubMedCrossRefGoogle Scholar
  125. 125.
    Okamura K, Matsubara F, Yoshioka Y, et al. Exercise-induced changes in branched chain amino acid/aromatic amino acid ratio in the rat brain and plasma. Jpn J Pharmacol 1987; 45 (2): 243–8PubMedCrossRefGoogle Scholar
  126. 126.
    Costill DL, Dalsky GP, Fink WJ. Effects of caffeine ingestion on metabolism and exercise performance. Med Sci Sports 1978; 10 (3): 155–8PubMedGoogle Scholar
  127. 127.
    Coyle EF. Carbohydrate feeding during exercise. Int J Sports Med 1992; 13 Suppl. 1: S126–8PubMedCrossRefGoogle Scholar
  128. 128.
    Nybo L, Moller K, Pedersen BK, et al. Association between fatigue and failure to preserve cerebral energy turnover during prolonged exercise. Acta Physiol Scand 2003; 179 (1): 67–74PubMedCrossRefGoogle Scholar
  129. 129.
    Dalsgaard MK, Ide K, Cai Y, et al. The intent to exercise influences the cerebral O(2)/carbohydrate uptake ratio in humans. J Physiol 2002; 540 (Pt 2): 681–9PubMedCrossRefGoogle Scholar
  130. 130.
    Kong J, Shepel PN, Holden CP, et al. Brain glycogen decreases with increased periods of wakefulness: implications for homeostatic drive to sleep. J Neurosci 2002; 22 (13): 5581–7PubMedGoogle Scholar
  131. 131.
    Dantzer R. Innate immunity at the forefront of psychoneuroimmunology. Brain Behav Immun 2004; 18 (1): 1–6PubMedCrossRefGoogle Scholar
  132. 132.
    Robson P. Elucidating the unexplained underperformance syndrome in endurance athletes: the interleukin-6 hypothesis. Sports Med 2003; 33 (10): 771–81PubMedCrossRefGoogle Scholar
  133. 133.
    Carmichael MD, Davis JM, Murphy EA, et al. Recovery of running performance following muscle-damaging exercise: Relationship to brain IL-1beta. Brain Behav Immun 2005 Sep; 19 (5): 445–52PubMedCrossRefGoogle Scholar
  134. 134.
    Steensberg A, van Hall G, Osada T, et al. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J Physiol 2000; 529 Pt 1: 237–42PubMedCrossRefGoogle Scholar
  135. 135.
    Pedersen BK, Steensberg A, Fischer C, et al. Searching for the exercise factor: is IL-6 a candidate? J Muscle Res Cell Motil 2003; 24 (2-3): 113–9PubMedCrossRefGoogle Scholar
  136. 136.
    Gleeson M. Interleukins and exercise. J Physiol 2000; 529 Pt 1: 1PubMedCrossRefGoogle Scholar
  137. 137.
    Nybo L, Nielsen B. Hyperthermia and central fatigue during prolonged exercise in humans. J Appl Physiol 2001; 91 (3): 1055–60PubMedGoogle Scholar
  138. 138.
    Nybo L, Nielsen B. Perceived exertion is associated with an altered brain activity during exercise with progressive hyperthermia. J Appl Physiol 2001; 91 (5): 2017–23PubMedGoogle Scholar
  139. 139.
    Nybo L, Nielsen B, Pedersen BK, et al. Interleukin-6 release from the human brain during prolonged exercise. J Physiol 2002; 542 (Pt 3): 991–5PubMedCrossRefGoogle Scholar
  140. 140.
    Marchi N, Rasmussen P, Kapural M, et al. Peripheral markers of brain damage and blood-brain barrier dysfunction. Restor Neurol Neurosci 2003; 21 (3,4): 109–21PubMedGoogle Scholar
  141. 141.
    Sharma HS, Cervos-Navarro J, Dey PK. Increased blood-brain barrier permeability following acute short-term swimming exercise in conscious normotensive young rats. Neurosci Res 1991; 10 (3): 211–21PubMedCrossRefGoogle Scholar
  142. 142.
    Sharma HS, Westman J, Navarro JC, et al. Probable involvement of serotonin in the increased permeability of the blood-brain barrier by forced swimming: an experimental study using Evans blue and 131I-sodium tracers in the rat. Behav Brain Res 1996; 72 (1-2): 189–96CrossRefGoogle Scholar
  143. 143.
    Watson P, Shirreffs SM, Maughan RJ. Blood-brain barrier integrity may be threatened by exercise in a warm environment. Am J Physiol Regul Integr Comp Physiol 2005; 288 (6): R1689–94PubMedCrossRefGoogle Scholar
  144. 144.
    Janal MN, Colt EW, Clark WC, et al. Pain sensitivity, mood and plasma endocrine levels in man following long-distance running: effects of naloxone. Pain 1984; 19 (1): 13–25PubMedCrossRefGoogle Scholar
  145. 145.
    Galloway SD, Maughan RJ. Effects of ambient temperature on the capacity to perform prolonged cycle exercise in man. Med Sci Sports Exerc 1997; 29 (9): 1240–9PubMedCrossRefGoogle Scholar
  146. 146.
    Parkin JM, Care MF, Zhao S, et al. Effect of ambient temperature on human skeletal muscle metabolism during fatiguing submaximal exercise. J Appl Physiol 1999; 86 (3): 902–8PubMedGoogle Scholar
  147. 147.
    Tatterson AJ, Hahn AG, Martin DT, et al. Effects of heat stress on physiological responses and exercise performance in elite cyclists. J Sci Med Sport 2000; 3 (2): 186–93PubMedCrossRefGoogle Scholar
  148. 148.
    Nielsen B. Heat stress causes fatigue! Exercise performance during acute and repeated exposures to hot, dry environments. In: Marconnet P, Komi PV, Saltin B, et al., editors. Muscle fatigue mechanisms in exercise and training. Basel: Karger, 1992: 207–17Google Scholar
  149. 149.
    Nielsen B, Nybo L. Cerebral changes during exercise in the heat. Sports Med 2003; 33 (1): 1–11PubMedCrossRefGoogle Scholar
  150. 150.
    Nielsen B, Hales JR, Strange S, et al. Human circulatory and thermoregulatory adaptations with heat acclimation and exercise in a hot, dry environment. J Physiol 1993; 460: 467–85PubMedGoogle Scholar
  151. 151.
    Gonzalez-Alonso J, Teller C, Andersen SL, et al. Influence of body temperature on the development of fatigue during prolonged exercise in the heat. J Appl Physiol 1999; 86 (3): 1032–9PubMedGoogle Scholar
  152. 152.
    Walters TJ, Ryan KL, Tate LM, et al. Exercise in the heat is limited by a critical internal temperature. J Appl Physiol 2000; 89 (2): 799–806PubMedGoogle Scholar
  153. 153.
    Armada-Da-Silva PA, Woods J, Jones DA. The effect of passive heating and face cooling on perceived exertion during exercise in the heat. Eur J Appl Physiol 2004; 91 (5-6): 563–71PubMedCrossRefGoogle Scholar
  154. 154.
    Drust B, Rasmussen P, Mohr M, et al. Elevations in core and muscle temperature impairs repeated sprint performance. Acta Physiol Scand 2005; 183 (2): 181–90PubMedCrossRefGoogle Scholar
  155. 155.
    Nielsen B, Hyldig T, Bidstrup F, et al. Brain activity and fatigue during prolonged exercise in the heat. Pflugers Arch 2001; 442 (1): 41–8PubMedCrossRefGoogle Scholar
  156. 156.
    Nybo L, Nielsen B. Middle cerebral artery blood velocity is reduced with hyperthermia during prolonged exercise in humans. J Physiol 2001; 534 (Pt 1): 279–86PubMedCrossRefGoogle Scholar
  157. 157.
    Nybo L, Secher NH, Nielsen B. Inadequate heat release from the human brain during prolonged exercise with hyperthermia. J Physiol 2002; 545 (Pt 2): 697–704PubMedCrossRefGoogle Scholar
  158. 158.
    Ftaiti F, Grelot L, Coudreuse JM, et al. Combined effect of heat stress, dehydration and exercise on neuromuscular function in humans. Eur J Appl Physiol 2001; 84 (1-2): 87–94PubMedCrossRefGoogle Scholar
  159. 159.
    Tucker R, Rauch L, Harley YX, et al. Impaired exercise performance in the heat is associated with an anticipatory reduction in skeletal muscle recruitment. Pflugers Arch 2004; 448 (4): 422–30PubMedCrossRefGoogle Scholar
  160. 160.
    Marino FE, Lambert MI, Noakes TD. Superior performance of African runners in warm humid but not in cool environmental conditions. J Appl Physiol 2004; 96 (1): 124–30PubMedCrossRefGoogle Scholar
  161. 161.
    Cheung SS, Sleivert GG. Multiple triggers for hyperthermic fatigue and exhaustion. Exerc Sport Sci Rev 2004; 32 (3): 100–6PubMedCrossRefGoogle Scholar
  162. 162.
    Ulmer HV. Concept of an extracellular regulation of muscular metabolic rate during heavy exercise in humans by psychophysiological feedback. Experientia 1996; 52 (5): 416–20PubMedCrossRefGoogle Scholar
  163. 163.
    Pitsiladis YP, Strachan AT, Davidson I, et al. Hyperprolactinaemia during prolonged exercise in the heat: evidence for a centrally mediated component of fatigue in trained cyclists. Exp Physiol 2002; 87 (2): 215–26PubMedCrossRefGoogle Scholar
  164. 164.
    Lin MT, Tsay HJ, Su WH, et al. Changes in extracellular serotonin in rat hypothalamus affect thermoregulatory function. Am J Physiol 1998; 274 (5 Pt 2): R1260–7PubMedGoogle Scholar
  165. 165.
    Lipton JM, Clark WG. Neurotransmitters in temperature control. Annu Rev Physiol 1986; 48: 613–23PubMedCrossRefGoogle Scholar
  166. 166.
    Hasegawa H, Yazawa T, Yasumatsu M, et al. Alteration in dopamine metabolism in the thermoregulatory center of exercising rats. Neurosci Lett 2000; 289 (3): 161–4PubMedCrossRefGoogle Scholar
  167. 167.
    Ishiwata T, Saito T, Hasegawa H, et al. Changes of body temperature and extracellular serotonin level in the preoptic area and anterior hypothalamus after thermal or serotonergic pharmacological stimulation of freely moving rats. Life Sci 2004; 75 (22): 2665–75PubMedCrossRefGoogle Scholar
  168. 168.
    Ishiwata T, Saito T, Hasegawa H, et al. Changes of body temperature and thermoregulatory responses of freely moving rats during GABAergic pharmacological stimulation to the preoptic area and anterior hypothalamus in several ambient temperatures. Brain Res 2005; 1048 (1-2): 32–40PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Romain Meeusen
    • 1
    Email author
  • Philip Watson
    • 2
  • Hiroshi Hasegawa
    • 1
    • 3
  • Bart Roelands
    • 1
  • Maria F. Piacentini
    • 1
    • 4
  1. 1.Department Human Physiology and Sportsmedicine, Faculty of Physical Education and PhysiotherapyVrije Universiteit BrusselBrusselsBelgium
  2. 2.School of Sport and Exercise SciencesLoughborough UniversityLeicestershireUK
  3. 3.Laboratory of Exercise Physiology, Faculty of Integrated Arts and SciencesHiroshima UniversityHigashihiroshimaJapan
  4. 4.Department of Human Movement and Sport SciencesIstituto Universitario di Scienze MotorieRomeItaly

Personalised recommendations