Int J Sports Med 2001; 22(7): 482-497
DOI: 10.1055/s-2001-17606
Review/Physiology and Biochemistry

© Georg Thieme Verlag Stuttgart · New York

Physiology and Pathophysiology of the Serotonergic System and its Implications on Mental and Physical Performance. Part II

H. K. Strüder1 , H. Weicker2
  • 1Institute of Theory and Practice of Training and Movement, German Sport University, Cologne, Germany
  • 2Department of Sports Medicine, Ruprecht-Karls-University, Heidelberg, Germany
Further Information

Publication History

Publication Date:
04 October 2001 (online)

As shown in the first part of this review, well equilibrated neurotransmission in which 5-HT plays a dominant role is important for proper neuromodulation and adjustment of neuronal network elements. Adequate 5-HT system function supports regulation of intercommunicative neuronal transmission in the brain, which optimizes behavioral neuromodulation during and after different forms of exertions, thereby preventing transient dysregulation. Impairment of neuromodulation and neuronal network in the brain with transient dysfunctions or permanent substantial deficits at manifestation of various types of depression results from prevalent impairment of 5-HT neurotransmission and its central interaction with other neurotransmitter systems. Exercise-induced increase of free tryptophan (TRP) in blood occurs due to liberation from albumin, which is caused by adrenergically induced lipolysis of free fatty acids and results in higher free TRP uptake into the brain. Consecutively enhanced serotonin (5-HT) biosynthesis does not per se initiate mood impairment or central fatigue. It is suggested that in overtrained athletes central fatigue, mental deficiency and behavioral alterations with depressive mood are probably not primarily caused by metabolic and neuromuscular alterations. The primary trigger of these transient behavioural alterations might instead be initiated by a central exhaustive exercise stress which elicits impairment of complex neuromodulation, also afflicting the interaction of central neurotransmitters or hypothalamic neuropeptides and releasing factors. In a consecutive correction of the variation, the implication of the serotonergic system on the central neuromodular disturbance might improve or prevent the progressive course both in transient and in permanent mental disorders. However, an unsuccessful attempt to improve the depressive symptomatology leads mostly to an overproportional exaggeration of the behavioral changes.


  • 1 Abdul-Rahman A, Dahlgren N, Johansson B B, Siesjö B K. Increase in local cerebral blood flow induced by circulating adrenaline. Involvement of blood-brain barrier dysfunction.  Acta Physiol Scand. 1979;  107 227-232
  • 2 Abele-Brehm A, Brehm W. Zur Konzeptualisierung und Messung von Befindlichkeit. Die Entwicklung der Befindlichkeitsskalen (BFS).  Diagnostica. 1986;  32 209
  • 3 Badawy A AB. The functions and regulation of tryptophan pyrrolase.  Life Sci. 1977;  21 755-768
  • 4 Badawy A AB, Evans M. Inhibition of rat liver trypotphan pyrrolase activity and elevation of brain tryptophan concentration by administration of antidepressants.  Biochemical Pharmacology. 1981;  30 1211-1216
  • 5 Badawy A AB, Morgan J. Tryptophan and tryptophan pyrrolase in haem regulation.  Biochem J. 1982;  206 451-460
  • 6 Bailey S P, Davis J M, Ahlborn E N. Effect of increased brain serotonergic activity on endurance performance in the rat.  Acta Physiol Scand. 1992;  145 75-76
  • 7 Bailey S P, Davis J M, Ahlborn E N. Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to fatigue.  J Appl Physiol. 1993;  74 3006-3012
  • 8 Bailey S P, Davis J M, Ahlborn E N. Serotonergic agonists and antagonists affect endurance performance in the rat.  Int J Sports Med. 1993;  14 330-333
  • 9 Banfi G, Marinelli M, Roi G S, Giacometti M. Platelet indices in athletes performing a race in altitude environment.  J Clin Lab Anal. 1995;  9 34-36
  • 10 Barron J L, Noakes T D, Levy W, Smith C, Millar R P. Hypothalamic dysfunction in overtrained athletes.  J Clin Endocrinol Metab. 1985;  60 803-806
  • 11 Baumgarten H G, Grozdanovic Z. Die Rolle des Serotonins in der Verhaltensmodulation.  Fortschr Neurol Psychiat. 1995;  63 3-8
  • 12 Baumgarten H G, Grozdanovic Z. Psychopharmacology of central serotonergic systems.  Pharmacopschiat. 1995;  28 73-79
  • 13 Biegon A, Weizman A, Karp L, Ram A, Tiano S, Wolff M. Serotonin 5-HT2 receptor binding on blood platelets - a peripheral marker for depression?.  Life Sci. 1987;  41 2485-2492
  • 14 Blomstrand E, Celsing F, Newsholme E A. Changes in plasma concentration of aromatic and branched chain amino acids during sustained exercise in man and their possible role in fatigue.  Acta Physiol Scand. 1988;  133 115-121
  • 15 Blomstrand E, Hassmén P, Ekblom B, Newsholme E A. Administration of branched-chain amino acids during sustained exercise - effects on performance and on plasma concentration of some amino acids.  Eur J Appl Physiol. 1991;  63 83-88
  • 16 Blomstrand E, Hassmén P, Newsholme E A. Effect of branched-chain amino acid supplementation on mental performance.  Acta Physiol Scand. 1991;  143 225-226
  • 17 Bond S W, Crabbe S, Sanders M C. Pharmacotherapy of eating disorders: a critical review.  Drug Intel Clin Pharm. 1986;  20 659-665
  • 18 Brewerton T D, Jimerson D C. Studies of serotonin function in anorexia nervosa.  Psychiatry Res. 1996;  62 31-42
  • 19 Calders P, Pannier J L, Matthys D M, Lacroix E M. Pre-exercise branched-chain amino acid administration increases endurance performance in rats.  Med Sci Sports Exerc. 1997;  29 1182-1186
  • 20 Chaouloff F. Physical exercise and brain monoamines: a review.  Acta Physiol Scand. 1989;  137 1-13
  • 21 Chaouloff F. Effects of acute physical exercise on central serotonergic systems.  Med Sci Sports Exerc. 1997;  29 58-62
  • 22 Chaouloff F, Elghozi J L, 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
  • 23 Chaouloff F, Kennett G A, Serrurier B, Merina D, Curzon G. Amino acid analysis demonstrates that increased plasma free tryptophan causes the increase of brain tryptophan during exercise in rat.  J Neurochem. 1986;  46 1647-1650
  • 24 Chaouloff F, Laude D, Elghozi J L. Physical exercise: evidence for differential consequences of tryptophan on 5-HT synthesis and metabolism in central serotonergic cell bodies and terminals.  J Neural Transm. 1989;  78 121-130
  • 25 Crow S J, Mitchell J E. Rational therapy of eating disorders.  Drugs. 1994;  48 372-379
  • 26 Da Prada M, Cesura A M, Launay J M, Richards J G. Platelets as a model for neurones?.  Experientia. 1988;  44 115-126
  • 27 Davids E, Lesch K P. Der 5-HT1A-Rezeptor: Ein neues Wirkprinzip psychopharmakologischer Therapiestrategien?.  Fortschr Neurol Psychiat. 1996;  64 460-472
  • 28 Davis J M. Carbohydrates, branched-chain amino acids, and endurance: the central fatigue hypothesis.  Int J Sport Nutr. 1995;  5 29-38
  • 29 Davis J M, Bailey S P. Possible mechanisms of central nervous system fatigue during exercise.  Med Sci Sports Exerc. 1997;  29 45-57
  • 30 Davis J M, Bailey S P, Jackson D A, Strasner A B, Morehouse S L. Effects of a serotonin (5-HT) agonist during prolonged exercise to fatigue in humans.  Med Sci Sports Exerc. 1993;  25 S78
  • 31 Davis J M, Bailey S P, Woods J A, Galiano F J, Hamilton M T, Bartoli W P. Effects of carbohydrate feedings on plasma free tryptophan and branched-chain amino acids during prolonged cycling.  Eur J Appl Physiol. 1992;  65 513-519
  • 32 De Palo E F, Metus P, Gatti R, Previti O, Bigon L, De Palo C B. Branched-chain amino acids chronic treatment and muscular exercise performance in athletes: a study through plasma acetyl-carnitine levels.  Amino Acids. 1993;  4 255-266
  • 33 Dixon G, Eurman P, Stern B E, Schwartz B, Rebar R W. Hypothalamic function in amenorrheic runners.  Fertility and Sterility. 1984;  42 377-383
  • 34 Dunn A, Dishmann R. Exercise and the neurobiology of depression.  Exerc Sport Sci Rev. 1991;  19 41-98
  • 35 Fernstrom J D, Wurtman R J. Brain serotonin content: physiological regulation by plasma neutral amino acids.  Science. 1971;  178 414-416
  • 36 Friedman P A, Kappelman A H, Kaufman S. Partial purification and characterization of tryptophan hydroxylase from rabbit hind brain.  J Biol Chem. 1972;  247 4165-4173
  • 37 Fry R W, Morton A R, Keast D. Overtraining in athletes.  Sports Med. 1991;  12 32-65
  • 38 Galiano F J, Davis J M, Baily S P, Woods J A, Hamilton M. Physiologic, endocrine and performance effects of adding branched chain amino acids to a 6 % carbohydrate-electrolyte beverage during prolonged cycling.  Med Sci Sports Exerc. 1991;  23 14
  • 39 Gleeson M, Blannin A K, Sewell D A. Short-term changes in the blood leucocyte and platelet count following different durations of high-intensity treadmill running.  J Sports Sci. 1995;  13 115-123
  • 40 Graeff F G. Serotonergic systems.  Psychiat Clin North America. 1997;  20 723-739
  • 41 Halmi K A. The state of research in anorexia nervosa and bulimia.  Psychiatric Developments. 1983;  3 247-262
  • 42 Han L, Nielsen D A, Rosenthal N E, Jefferson K, Kaye W, Murphy D, Altemus M, Humphries J, Cassano G, Rotondo A, Virkkunen M, Linnoila M, Goldman D. No coding variant of the tryptophan hydroxylase gene detected in seasonal affective disorder, obsessive-compulsive disorder, anorexia nervosa, and alcoholism.  Biol Psychiatry. 1999;  45 615-619
  • 43 Hassmén P, Blomstrand E, Ekblom B, Newsholme E A. Branched-chain amino acid supplementation during 3-km competitive run: mood and cognitive performance.  Nutrition. 1994;  10 405-410
  • 44 Hefler S K, Wideman L, Gaesser G A, Weltman A. Branched-chain amino acid (BCAA) supplementation improves endurance performance in competitive cyclists.  Med Sci Sports Exerc. 1995;  27 S 149
  • 45 Hoyer D. International union of pharmacology classification of receptors for 5-hydroxytryptamine (serotonin).  Pharmacol Rev. 1993;  46 157
  • 46 Hoyer D, Middlemiss D N. The pharmacology of the terminal 5-HT autoreceptors in mammalian brain: evidence for species differences.  Trends Pharmacol Sci. 1989;  10 130-132
  • 47 Hudson J I, Pope H G, Jonas M D, Yurgelun-Todd D. Treatment of anorexia nervosa with antidepressants.  J Clin Psychopharmacol. 1985;  5 17-23
  • 48 Jakeman P M, Hawthorne J E, Maxwell S RJ, Kendall M J, Holder G. Evidence for downregulation of hypothalamic 5-hydroxytryptamine receptor function in endurance-trained athletes.  Exper Physiol. 1994;  79 461-464
  • 49 Kaplan L M. Herrisons principles of internal medicine. Grayhill 1998: 584-592
  • 50 Kaye W, Gendall K, Strober M. Serotonin neuronal function and selective serotonin reuptake inhibitor treatment in anorexia and bulimia nervosa.  Biol Psychiatry. 1998;  44 825-838
  • 51 Keizer H A. Hormonal responses in women as a function of physical exercise and training.  Int J Sports Med. 1987;  8 137-174
  • 52 Kreider R B, Miriel V, Bertun E. Amino acid supplementation and exercise performance. Analysis of the proposed ergogenic value.  Sports Med. 1993;  16 190-209
  • 53 Kuipers H, Keizer H A. Overtraining in elite athletes: review and directions for the future.  Sports Med. 1988;  6 79-92
  • 54 Lambert M, Velloza P, Wilson G. The effect of carbohydrate and branched-chain amino acid supplementation on cycling performance and mental fatigue. Aberdeen; 9th Int. Conference Biochemistry of Exercise 1994: 53
  • 55 Lehmann M, Gastmann U, Petersen K G, Bachl N, Seidel A, Khalaf A K, Fischer S, Keul J. Training-overtraining: performance, and hormone levels, after a defined increase in training volume versus intensity in experienced middle- and long-distance runners.  Br J Sport Med. 1992;  26 233-242
  • 56 Leibowitz S F. The role of serotonin in eating disorders.  Drugs. 1990;  39 33-48
  • 57 Litt I F, Glader L. Anorexia nervosa, athletics, and amenorrhea.  J Pediatrics. 1986;  109 150-153
  • 58 Long D, Blake M, McNaughton L, Angle B. Hematological and biochemical changes during a short triathlon competition in novice triathletes.  Eur J Appl Physiol. 1990;  61 93-99
  • 59 Madsen K, Christensen D. Administration of glucose, glucose plus branched-chain amino acids or placebo during sustained exercise and their effects on a 100 km bike performance. Aberdeen; 9th Int. Conference Biochemistry of Exercise 1994: 35
  • 60 Mans A M, Biebuyck J F, Hawkins R A. Ammonia selectively stimulates neutral amino acid transport across blood-brain barrier.  Am J Physiol. 1983;  245 C74-C77
  • 61 Marvin G, Sharma A, Aston W, Field C, Kendall M J, Jones D A. The effects of buspirone on perceived exertion and time to fatigue in man.  Exp Physiol. 1997;  82 1057-1060
  • 62 McMenamy R H. Binding of indole analogues to human serum albumin. Effects of fatty acids.  J Biol Chem. 1965;  240 4235-4243
  • 63 McMenamy R H, Oncley J L. The specific binding of L-tryptophan to serum albumin.  J Biol Chem. 1958;  233 1436-1447
  • 64 Meeusen R, De Meirleir K. Exercise and brain neurotransmission.  Sports Med. 1995;  20 160-188
  • 65 Meeusen R, Roeykens J, Magnus L, Keizer H, De Meirleir K. Endurance performance in humans: the effect of a dopamine precursor or a specific serotonin (5-HT2A/2C) antagonist.  Int J Sports Med. 1997;  18 571-577
  • 66 Mittleman K D, Ricci M R, Bailey S P. Branched-chain amino acids prolong exercise during heat stress in men and women.  Med Sci Sports Exerc. 1998;  30 83-91
  • 67 Monteleone P, Brambilla F, Bortolotti F, LaRocca A, Maj M. Prolactin response to d-fenfluramine is blunted in people with anorexia nervosa.  Brit J Psychiatry. 1998;  172 438-442
  • 68 Murphy D L, Andrews A M, Wichems C H, Li Q, Tohda M, Greenberg B. Brain serotonin neurotransmission: an overview and update with an emphasis on serotonin subsystem heterogeneity, multiple receptors, interactions with other neurotransmitter systems, and consequent implications for understanding the actions of serotonergic drugs.  1998;  59 4-12
  • 69 Nathanson J A. Adrenergic receptors in brain microvessels.  Trends Neurol Sci. 1983;  4 422-425
  • 70 Neumärker K J, Bartsch A J. Anorexia nervosa und “anorexia athletica”?. WMW 1998: 245-250
  • 71 Newsholme E A, Acworth I N, Blomstrand E. Amino acids, brain neurotransmitters and a functional link between muscle and brain that is important in sustained exercise. In: Benzi G (ed) Advances in Myochemistry. London; John Libbey Eurotext 1987: 127-133
  • 72 Newsholme E A, Blomstrand E, Hassmén P, Ekblom B. Physical and mental fatigue: do changes in plasma amino acids play a role?.  Biochem Soc Trans. 1991;  19 358-362
  • 73 Nicholls J G, Martin A R, Wallace B G. Vom Neuron zum Gehirn. Stuttgart; Fischer 1995: 176-203
  • 74 Nitsch J R. Die Eigenzustandsskala (EZ-Skala) - Ein Verfahren zur hierarchisch-mehrdimensionalen Befindlichkeitsskalierung. In: Nitsch JR, Udris I (eds) Beanspruchung im Sport. Bad Homburg; Limpert 1976: 81-102
  • 75 Owens M J, Nemeroff C B. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter.  Clin Chem. 1994;  40 288-295
  • 76 Pannier J L, Bouckaert J J, Lefebvre R A. The antiserotonin agent pizotifen does not increase endurance performance in humans.  Eur J Appl Physiol. 1995;  72 175-178
  • 77 Pletscher A. The 5-hydroxytryptamine system of blood platelets: physiology and pathophysiology.  Int J Cardiol. 1987;  14 177-188
  • 78 Rudnick G, Clark H. From synapse to vesicle: the reuptake and storage of biogenic amine neurotransmitters.  Biochim Biophys Acta. 1993;  1144 249-263
  • 79 Segura R, Ventura J L. Effect of L-tryptophan supplementation on exercise performance.  Int J Sports Med. 1988;  9 301-305
  • 80 Sheline Y l, Bardgett M E, Jackson J L, Newcomer H W, Csernansky I G. Platelet serotonin markers and depressive symptomatology.  Biol Psychiatry. 1995;  37 442-447
  • 81 Sourkes T L. Toxicology of serotonin precursors.  Adv Biol Psychiat. 1983;  10 160-175
  • 82 Spector A A. Fatty acid binding to plasma albumin.  J Lipid Res. 1975;  16 165-179
  • 83 Spigset O, Mjörndal T. Serotonin 5-HT2A receptor binding in platelets from healthy subjects as studied by [3H]-lysergic acid diethylamide ([3H]-LSD): intra- and interindividual variability.  Neuropsychopharmacol. 1997;  16 285-293
  • 84 Stensrud T, Ingjer F, Holm H, Strømme S B. L-tryptophan supplementation does not improve running performance.  Int J Sports Med. 1992;  13 481-485
  • 85 Støving R K, Hangaard J, Hansen-Nord M, Hagen C. A review of endocrine changes in anorexia nervosa.  J Psychiatric Res. 1999;  33 139-152
  • 86 Strachan A T, Maughan R J. Platelet serotonin transporter density and related parameters in endurance-trained and sedentary male subjects.  Acta Physiol Scand. 1998;  163 165-171
  • 87 Strachan A T, Maughan R J. The hormonal response to a d-fenfluramine challenge in trained and sedentary men.  Med Sci Sports Med. 1999;  31 547-553
  • 88 Strüder H K. Influence of muscular work on brain metabolism and psyche in trained and untrained males of different ages. The monoaminergic and neuroendocrine system. Cologne; German Sport University Cologne 2000
  • 89 Strüder H K, Ferrauti A, Gotzmann A, Weber K, Hollmann W. Effect of carbohydrates and caffeine on plasma amino acids, neuroendocrine responses and performance in tennis.  Nutr Neurosci. 1998;  1 419-426
  • 90 Strüder H K, Hollmann W, Donike M, Platen P, Weber K. Effect of O2 availability on neuroendocrine variables at rest and during exercise: O2 breathing increases plasma prolactin.  Eur J Appl Physiol. 1996;  74 443-449
  • 91 Strüder H K, Hollmann W, Duperly J, Weber K. Amino acid metabolism in tennis and its possible influence on the neuroendocrine system.  Br J Sp Med. 1995;  29 28-30
  • 92 Strüder H K, 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
  • 93 Strüder H K, Hollmann W, Platen P, Duperly J, Fischer H G, Weber K. Alterations in plasma free tryptophan and large neutral amino acids do not affect perceived exertion and prolactin during 90min of treadmill exercise.  Int J Sports Med. 1996;  17 73-79
  • 94 Strüder H K, Hollmann W, Platen P, Rost R, Weicker H, Kirchhof O, Weber K. Neuroendocrine system and mental function in sedentary and endurance-trained elderly males.  Int J Sports Med. 1999;  20 159-166
  • 95 Strüder H K, Hollmann W, Platen P, Wöstmann R, Donike M, Weber K. Einfluss von Paroxetin, verzweigtkettingen Aminosäuren und Tyrosin auf das endocrine System und die körperliche Leistungsfähigkeit.  Dtsch Z Sportmed. 1995;  46 458-463
  • 96 Strüder H, Hollmann W, Platen P, Wöstmann R, Ferrauti A, Weber K. Effects of exercise intensity on free tryptophan to branched-chain amino acids ratio and plasma prolactin during endurance exercise.  Can J Appl Physiol. 1997;  22 280-291
  • 97 Strüder H K, Hollmann W, Platen P, Wöstmann R, Weicker H, Molderings G H. Effect of acute and chronic exercise on plasma amino acids and prolactin concentrations and on [3H]ketanserin binding to 5-HT2A receptors on human platelets.  Eur J Appl Physiol. 1999;  79 318-324
  • 98 Strüder H K, Hollmann W, Weicker H, Strobel G, Platen P, Heck H, Hartmann U, Bartmus U, Grabow V, Schulz H, Wöstmann R, Weber K. Influence of moderate and excessive endurance training on the serotonergic system.  Int J Sports Med. 1999;  20 S38
  • 99 Sundgot-Borgen J. Nutrient intake of female elite athletes suffering from eating disorders.  Int J Sport Nutrition. 1993;  3 431-442
  • 100 Sundgot-Borgen J. Eating disorders, energy intake, training volume and menstrual function in high-level modern rhythmic gymnasts.  Int J Sport Nutrition. 1996;  6 100-109
  • 101 Takikawa O, Kuroiwa T, Yamazahki F, Kido R. Function and regulation of extrahepatic tryptophan pyrrolase (indoleamine 2,3-dioxygenase): studies of its induction by interferon-γ. In: Bender DA, Joseph MH, Kochen W, Steinhart H (eds) Progress in tryptophan and serotonin research 1986. Berlin; De Gruyter 1987: 47-52
  • 102 Urhausen A, Kindermann W. Current markers for the diagnosis of overtraining in sports practice.  Int J Sports Med. 1999;  20 S54
  • 103 Van Hall G, Raaymakers J SH, Saris W HM, Wagenmakers A JM. Ingestion of branched-chain amino acids and tryptophan during sustained exercise in man: failure to affect performance.  J Physiol. 1995;  486 789-794
  • 104 Van Wersch J WJ, Kaiser V, Janssen G ME. Platelet system changes associated with a training period of 18 - 20 months: a transverse and a longitudinal approach.  Int J Sports Med. 1989;  10 S181-S185
  • 105 Varnier M, Sarto P, Martines D, Lora L, Carmignoto F, Leese G P, Naccarato R. Effect of infusing branched-chain amino acid during incremental exercise with reduced muscle glycogen content.  Eur J Appl Physiol. 1994;  69 26-31
  • 106 Verger P, Aymard P, Cynobert L, Anton G, Luigi R. Effects of administration of branched-chain amino acids vs glucose during acute exercise in the rat.  Physiol Behav. 1994;  55 523-526
  • 107 Weicker H, Strobel G. Sportmedizin - biochemisch-physiologische Grundlagen und ihre sportartspezifische Bedeutung. Stuttgart, Jena, New York; Fischer 1994
  • 108 Wilson W M, Maughan R J. 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;  77 921-924

PD Dr. H. K. Strüder

Institute of Theory and Practice of Training and Movement
German Sport University

Carl-Diem-Weg 6
50933 Cologne

Phone: +49 (221) 4995818

Fax: +49 (221) 4995818