Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Feature Review
  • Published:

Mechanism of acute tryptophan depletion: is it only serotonin?

Molecular Psychiatry volume 16, pages 695–713 (2011)Cite this article

Subjects

Abstract

The method of acute tryptophan depletion (ATD), which reduces the availability of the essential amino acid tryptophan (TRP), the dietary serotonin (5-hydroxytryptamine (5-HT)) precursor, has been applied in many experimental studies. ATD application leads to decreased availability of TRP in the brain and its synthesis into 5-HT. It is therefore assumed that a decrease in 5-HT release and subsequent blunted neurotransmission is the underlying mechanism for the behavioural effects of ATD. However, direct evidence that ATD decreases extracellular 5-HT concentrations is lacking. Furthermore, several studies provide support for alternative underlying mechanisms of ATD. This may question the utility of the method as a selective serotonergic challenge tool. As ATD is extensively used for investigating the role of 5-HT in cognitive functions and psychiatric disorders, the potential of alternative mechanisms and possible confounding factors should be taken into account. It is suggested that caution is required when interpreting ATD effects in terms of a selective serotonergic effect.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Fadda F, Cocco S, Stancampiano R . A physiological method to selectively decrease brain serotonin release. Brain Res Brain Res Protoc 2000; 5: 219–222.

    Article  CAS  PubMed  Google Scholar 

  2. Blokland A, Lieben C, Deutz NEP, Schmitt J . Acute Tryptophan depletion: comparing the effects of an amino acid mixture with a gelatin-based protein in man and rats. Curr Top Nutraceut R 2004; 2: 1–8.

    Google Scholar 

  3. Feenstra MG, van der Plasse G . Tryptophan depletion and serotonin release - a critical reappraisal. In: Muller CP, Jacobs B (eds). Handbook of the Behavioral Neurobiology of Serotonin, vol. 21. Academic Press: London, 2010, pp 249–258.

    Chapter  Google Scholar 

  4. Jans LA, Riedel WJ, Markus CR, Blokland A . Serotonergic vulnerability and depression: assumptions, experimental evidence and implications. Mol Psychiatry 2007; 12: 522–543.

    Article  CAS  PubMed  Google Scholar 

  5. Booij L, Van der Does AJ, Riedel WJ . Monoamine depletion in psychiatric and healthy populations: review. Mol Psychiatry 2003; 8: 951–973.

    Article  CAS  PubMed  Google Scholar 

  6. Ruhe HG, Mason NS, Schene AH . Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry 2007; 12: 331–359.

    Article  CAS  PubMed  Google Scholar 

  7. Oldendorf WH . Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am J Physiol 1971; 221: 1629–1639.

    Article  CAS  PubMed  Google Scholar 

  8. Pardridge WM . Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids. Neurochem Res 1998; 23: 635–644.

    Article  CAS  PubMed  Google Scholar 

  9. Smith QR . Transport of glutamate and other amino acids at the blood-brain barrier. J Nutr 2000; 130 (4S Suppl): 1016S–1122S.

    Article  CAS  PubMed  Google Scholar 

  10. Fernstrom JD, Wurtman RJ . Brain serotonin content: physiological dependence on plasma tryptophan levels. Science 1971; 173: 149–152.

    Article  CAS  PubMed  Google Scholar 

  11. Fernstrom JD, Wurtman RJ . Brain serotonin content: physiological regulation by plasma neutral amino acids. Science 1972; 178: 414–416.

    Article  CAS  PubMed  Google Scholar 

  12. Gessa GL, Biggio G, Fadda F, Corsini GU, Tagliamonte A . Effect of the oral administration of tryptophan-free amino acid mixtures on serum tryptophan, brain tryptophan and serotonin metabolism. J Neurochem 1974; 22: 869–870.

    Article  CAS  PubMed  Google Scholar 

  13. Fernstrom JD . Role of precursor availability in control of monoamine biosynthesis in brain. Physiol Rev 1983; 63: 484–546.

    Article  CAS  PubMed  Google Scholar 

  14. Fernstrom JD . Diet-induced changes in plasma amino acid pattern: effects on the brain uptake of large neutral amino acids, and on brain serotonin synthesis. J Neural Transm Suppl 1979; 15: 55–67.

    CAS  Google Scholar 

  15. Biggio G, Fadda F, Fanni P, Tagliamonte A, Gessa GL . Rapid depletion of serum tryptophan, brain tryptophan, serotonin and 5-hydroxyindoleacetic acid by a tryptophan-free diet. Life Sci 1974; 14: 1321–1329.

    Article  CAS  PubMed  Google Scholar 

  16. Oldendorf WH, Szabo J . Amino acid assignment to one of three blood-brain barrier amino acid carriers. Am J Physiol 1976; 230: 94–98.

    Article  CAS  PubMed  Google Scholar 

  17. Tagliamonte A, Biggio G, Vargiu L, Gessa GL . Free tryptophan in serum controls brain tryptophan level and serotonin synthesis. Life Sci 2 1973; 12: 277–287.

    Article  CAS  Google Scholar 

  18. Gessa GL, Tagliamonte A . Possible role of free serum tryptophan in the control of brain tryptophan level and serotonin synthesis. Adv Biochem Psychopharmacol 1974; 11: 119–131.

    CAS  PubMed  Google Scholar 

  19. Bender DA . Biochemistry of tryptophan in health and disease. Mol Aspects Med 1983; 6: 101–197.

    Article  CAS  PubMed  Google Scholar 

  20. Reed RG, Burrington CM . The albumin receptor effect may be due to a surface-induced conformational change in albumin. J Biol Chem 1989; 264: 9867–9872.

    CAS  PubMed  Google Scholar 

  21. Pardridge WM, Fierer G . Transport of tryptophan into brain from the circulating, albumin-bound pool in rats and in rabbits. J Neurochem 1990; 54: 971–976.

    Article  CAS  PubMed  Google Scholar 

  22. Smith QR, Momma S, Aoyagi M, Rapoport SI . Kinetics of neutral amino acid transport across the blood-brain barrier. J Neurochem 1987; 49: 1651–1658.

    Article  CAS  PubMed  Google Scholar 

  23. Ruddick JP, Evans AK, Nutt DJ, Lightman SL, Rook GA, Lowry CA . Tryptophan metabolism in the central nervous system: medical implications. Expert Rev Mol Med 2006; 8: 1–27.

    Article  PubMed  Google Scholar 

  24. Lieben CK, Blokland A, Westerink B, Deutz NE . Acute tryptophan and serotonin depletion using an optimized tryptophan-free protein-carbohydrate mixture in the adult rat. Neurochem Int 2004; 44: 9–16.

    Article  CAS  PubMed  Google Scholar 

  25. Fusar-Poli P, Allen P, McGuire P, Placentino A, Cortesi M, Perez J . Neuroimaging and electrophysiological studies of the effects of acute tryptophan depletion: a systematic review of the literature. Psychopharmacology (Berl) 2006; 188: 131–143.

    Article  CAS  Google Scholar 

  26. Van der Does AJ . The mood-lowering effect of tryptophan depletion: possible explanation for discrepant findings. Arch Gen Psychiatry 2001; 58: 200–202.

    Article  CAS  PubMed  Google Scholar 

  27. Evers EA, Tillie DE, van der Veen FM, Lieben CK, Jolles J, Deutz NE et al. Effects of a novel method of acute tryptophan depletion on plasma tryptophan and cognitive performance in healthy volunteers. Psychopharmacology 2005; 178: 92–99.

    Article  CAS  PubMed  Google Scholar 

  28. Sambeth A, Riedel W, Tillie D, Blokland A, Postma A, Schmitt J . Memory impairments in humans after acute tryptophan depletion using a novel gelatin-based protein drink. J Psychopharmacol 2009; 23: 56–64.

    Article  CAS  PubMed  Google Scholar 

  29. Djagny VB, Wang Z, Xu S . Gelatin: a valuable protein for food and pharmaceutical industries: review. Crit Rev Food Sci Nutr 2001; 41: 481–492.

    Article  CAS  PubMed  Google Scholar 

  30. Markus CR, Panhuysen G, Tuiten A, Koppeschaar H, Fekkes D, Peters ML . Does carbohydrate-rich, protein-poor food prevent a deterioration of mood and cognitive performance of stress-prone subjects when subjected to a stressful task? Appetite 1998; 31: 49–65.

    Article  CAS  PubMed  Google Scholar 

  31. Markus CR . Effects of carbohydrates on brain tryptophan availability and stress performance. Biol Psychol 2007; 76: 83–90.

    Article  CAS  PubMed  Google Scholar 

  32. Benton D . Carbohydrate ingestion, blood glucose and mood. Neurosci Biobehav Rev 2002; 26: 293–308.

    Article  CAS  PubMed  Google Scholar 

  33. Fernstrom JD, Wurtman RJ . Elevation of plasma tryptophan by insulin in rat. Metabolism 1972; 21: 337–342.

    Article  CAS  PubMed  Google Scholar 

  34. Fernstrom JD, Fernstrom MH, Grubb PE . Twenty-four-hour variations in rat blood and brain levels of the aromatic and branched-chain amino acids: chronic effects of dietary protein content. Metabolism 1987; 36: 643–650.

    Article  CAS  PubMed  Google Scholar 

  35. Teff KL, Young SN, Blundell JE . The effect of protein or carbohydrate breakfasts on subsequent plasma amino acid levels, satiety and nutrient selection in normal males. Pharmacol, Biochem Behav 1989; 34: 829–837.

    Article  CAS  Google Scholar 

  36. Harper AE, Benevenga NJ, Wohlhueter RM . Effects of ingestion of disproportionate amounts of amino acids. Physiol Rev 1970; 50: 428–558.

    Article  CAS  PubMed  Google Scholar 

  37. Gessa GL, Biggio G, Fadda F, Corsini GU, Tagliamonte A . Tryptophan-free diet: a new means for rapidly decreasing brain tryptophan content and serotonin synthesis. Acta Vitaminol Enzymol 1975; 29: 72–78.

    CAS  PubMed  Google Scholar 

  38. Moja EA, Restani P, Corsini E, Stacchezzini MC, Assereto R, Galli CL . Cycloheximide blocks the fall of plasma and tissue tryptophan levels after tryptophan-free amino acid mixtures. Life Sci 1991; 49: 1121–1128.

    Article  CAS  PubMed  Google Scholar 

  39. Neumeister A . Tryptophan depletion, serotonin, and depression: where do we stand? Psychopharmacol Bull 2003; 37: 99–115.

    PubMed  Google Scholar 

  40. Bell CJ, Hood SD, Nutt DJ . Acute tryptophan depletion. Part II: clinical effects and implications. Aust N Z J Psychiatry 2005; 39: 565–574.

    Article  PubMed  Google Scholar 

  41. Hood SD, Bell CJ, Nutt DJ . Acute tryptophan depletion. Part I: rationale and methodology. Aust N Z J Psychiatry 2005; 39: 558–564.

    Article  PubMed  Google Scholar 

  42. Young SN . The use of diet and dietary components in the study of factors controlling affect in humans: a review. J Psychiatry Neurosci 1993; 18: 235–244.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Reilly JG, McTavish SF, Young AH . Rapid depletion of plasma tryptophan: a review of studies and experimental methodology. J Psychopharmacol 1997; 11: 381–392.

    Article  CAS  PubMed  Google Scholar 

  44. Leonard BE . Fundamentals of Psychopharmacology, 2nd edn. Wiley and Sons: New York, 1997.

    Google Scholar 

  45. Maes M, Meltzer HY . The Serotonin Hypothesis of Major Depression. Raven Press, Ltd: New York, 1995, pp 933–944.

    Google Scholar 

  46. Meltzer HY . Role of serotonin in depression. Ann NY Acad Sci 1990; 600: 486–499; discussion 499–500.

    Article  CAS  PubMed  Google Scholar 

  47. Steinbusch HW . Distribution of serotonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals. Neuroscience 1981; 6: 557–618.

    Article  CAS  PubMed  Google Scholar 

  48. Cowen PJ, Parry-Billings M, Newsholme EA . Decreased plasma tryptophan levels in major depression. J Affect Disord 1989; 16: 27–31.

    Article  CAS  PubMed  Google Scholar 

  49. Asberg M, Traskman L, Thoren P . 5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor? Arch Gen Psychiatry 1976; 33: 1193–1197.

    Article  CAS  PubMed  Google Scholar 

  50. van Praag HM, de Haan S . Central serotonin metabolism and frequency of depression. Psychiatry Res 1979; 1: 219–224.

    Article  CAS  PubMed  Google Scholar 

  51. Naughton M, Mulrooney JB, Leonard BE . A review of the role of serotonin receptors in psychiatric disorders. Hum Psychopharmacol 2000; 15: 397–415.

    Article  CAS  PubMed  Google Scholar 

  52. Cryan JF, Leonard BE . 5-HT1A and beyond: the role of serotonin and its receptors in depression and the antidepressant response. Hum Psychopharmacol 2000; 15: 113–135.

    Article  CAS  PubMed  Google Scholar 

  53. Neumeister A, Konstantinidis A, Stastny J, Schwarz MJ, Vitouch O, Willeit M et al. Association between serotonin transporter gene promoter polymorphism (5HTTLPR) and behavioral responses to tryptophan depletion in healthy women with and without family history of depression. Arch Gen Psychiatry 2002; 59: 613–620.

    Article  CAS  PubMed  Google Scholar 

  54. Klaassen T, Riedel WJ, van Someren A, Deutz NE, Honig A, van Praag HM . Mood effects of 24-hour tryptophan depletion in healthy first-degree relatives of patients with affective disorders. Biol Psychiatry 1999; 46: 489–497.

    Article  CAS  PubMed  Google Scholar 

  55. Smith KA, Fairburn CG, Cowen PJ . Relapse of depression after rapid depletion of tryptophan. Lancet 1997; 349: 915–919.

    Article  CAS  PubMed  Google Scholar 

  56. Ellenbogen MA, Young SN, Dean P, Palmour RM, Benkelfat C . Mood response to acute tryptophan depletion in healthy volunteers: sex differences and temporal stability. Neuropsychopharmacology 1996; 15: 465–474.

    Article  CAS  PubMed  Google Scholar 

  57. Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, de Montigny C et al. Differences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci USA 1997; 94: 5308–5313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Neumeister A, Nugent AC, Waldeck T, Geraci M, Schwarz M, Bonne O et al. Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. Arch Gen Psychiatry 2004; 61: 765–773.

    Article  CAS  PubMed  Google Scholar 

  59. Moreno FA, Gelenberg AJ, Heninger GR, Potter RL, McKnight KM, Allen J et al. Tryptophan depletion and depressive vulnerability. Biol Psychiatry 1999; 46: 498–505.

    Article  CAS  PubMed  Google Scholar 

  60. Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR . Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 1990; 47: 411–418.

    Article  CAS  PubMed  Google Scholar 

  61. Delgado PL, Price LH, Miller HL, Salomon RM, Licinio J, Krystal JH et al. Rapid serotonin depletion as a provocative challenge test for patients with major depression: relevance to antidepressant action and the neurobiology of depression. Psychopharmacol Bull 1991; 27: 321–330.

    CAS  PubMed  Google Scholar 

  62. Delgado PL, Miller HL, Salomon RM, Licinio J, Krystal JH, Moreno FA et al. Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiatry 1999; 46: 212–220.

    Article  CAS  PubMed  Google Scholar 

  63. Delgado PL, Charney DS, Price LH, Landis H, Heninger GR . Neuroendocrine and behavioral effects of dietary tryptophan restriction in healthy subjects. Life Sci 1989; 45: 2323–2332.

    Article  CAS  PubMed  Google Scholar 

  64. Young SN, Smith SE, Pihl RO, Ervin FR . Tryptophan depletion causes a rapid lowering of mood in normal males. Psychopharmacology (Berl) 1985; 87: 173–177.

    Article  CAS  Google Scholar 

  65. Carpenter LL, Anderson GM, Pelton GH, Gudin JA, Kirwin PD, Price LH et al. Tryptophan depletion during continuous CSF sampling in healthy human subjects. Neuropsychopharmacology 1998; 19: 26–35.

    Article  CAS  PubMed  Google Scholar 

  66. Evers EA, van der Veen FM, Jolles J, Deutz NE, Schmitt JA . Acute tryptophan depletion improves performance and modulates the BOLD response during a Stroop task in healthy females. Neuroimage 2006; 32: 248–255.

    Article  CAS  PubMed  Google Scholar 

  67. Moore P, Landolt HP, Seifritz E, Clark C, Bhatti T, Kelsoe J et al. Clinical and physiological consequences of rapid tryptophan depletion. Neuropsychopharmacology 2000; 23: 601–622.

    Article  CAS  PubMed  Google Scholar 

  68. Williams WA, Shoaf SE, Hommer D, Rawlings R, Linnoila M . Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers. J Neurochem 1999; 72: 1641–1647.

    Article  CAS  PubMed  Google Scholar 

  69. Moreno FA, McGavin C, Malan TP, Gelenberg AJ, Heninger GR, Mathe AA et al. Tryptophan depletion selectively reduces CSF 5-HT metabolites in healthy young men: results from single lumbar puncture sampling technique. Int J Neuropsychopharmacol 2000; 3: 277–283.

    Article  CAS  PubMed  Google Scholar 

  70. Booij L, Van der Does AJ, Haffmans PM, Riedel WJ, Fekkes D, Blom MJ . The effects of high-dose and low-dose tryptophan depletion on mood and cognitive functions of remitted depressed patients. J Psychopharmacol 2005; 19: 267–275.

    Article  CAS  PubMed  Google Scholar 

  71. Sambeth A, Blokland A, Harmer CJ, Kilkens TO, Nathan PJ, Porter RJ et al. Sex differences in the effect of acute tryptophan depletion on declarative episodic memory: a pooled analysis of nine studies. Neurosci Biobehav Rev 2007; 31: 516–529.

    Article  CAS  PubMed  Google Scholar 

  72. Klaassen T, Riedel WJ, Deutz NE, van Someren A, van Praag HM . Specificity of the tryptophan depletion method. Psychopharmacology 1999; 141: 279–286.

    Article  CAS  PubMed  Google Scholar 

  73. Riedel WJ . Cognitive changes after acute tryptophan depletion: what can they tell us? Psychol Med 2004; 34: 3–8.

    Article  PubMed  Google Scholar 

  74. Riedel WJ, Klaassen T, Deutz NE, van Someren A, van Praag HM . Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation. Psychopharmacology (Berl) 1999; 141: 362–369.

    Article  CAS  Google Scholar 

  75. Mendelsohn D, Riedel WJ, Sambeth A . Effects of acute tryptophan depletion on memory, attention and executive functions: a systematic review. Neurosci Biobehav Rev 2009; 33: 926–952.

    Article  CAS  PubMed  Google Scholar 

  76. van der Staay FJ . Animal models of behavioral dysfunctions: basic concepts and classifications, and an evaluation strategy. Brain Res Rev 2006; 52: 131–159.

    Article  PubMed  Google Scholar 

  77. Blokland A, Lieben C, Deutz NE . Anxiogenic and depressive-like effects, but no cognitive deficits, after repeated moderate tryptophan depletion in the rat. J Psychopharmacol 2002; 16: 39–49.

    Article  CAS  PubMed  Google Scholar 

  78. Cahir M, Ardis T, Reynolds GP, Cooper SJ . Acute and chronic tryptophan depletion differentially regulate central 5-HT1A and 5-HT 2A receptor binding in the rat. Psychopharmacology 2007; 190: 497–506.

    Article  CAS  PubMed  Google Scholar 

  79. Jans LA, Lieben CK, Blokland A . Influence of sex and estrous cycle on the effects of acute tryptophan depletion induced by a gelatin-based mixture in adult Wistar rats. Neuroscience 2007; 147: 304–317.

    Article  CAS  PubMed  Google Scholar 

  80. Olivier JD, Jans LA, Korte-Bouws GA, Korte SM, Deen PM, Cools AR et al. Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats. Psychopharmacology (Berl) 2008; 200: 243–254.

    Article  CAS  Google Scholar 

  81. van Donkelaar EL, Ferrington L, Blokland A, Steinbusch HW, Prickaerts J, Kelly PA . Acute tryptophan depletion in rats alters the relationship between cerebral blood flow and glucose metabolism independent of central serotonin. Neuroscience 2009; 163: 683–694.

    Article  CAS  PubMed  Google Scholar 

  82. van Donkelaar EL, van den Hove DL, Blokland A, Steinbusch HW, Prickaerts J . Stress-mediated decreases in brain-derived neurotrophic factor as potential confounding factor for acute tryptophan depletion-induced neurochemical effects. Eur Neuropsychopharmacol 2009; 19: 812–821.

    Article  CAS  PubMed  Google Scholar 

  83. Lieben CK, van Oorsouw K, Deutz NE, Blokland A . Acute tryptophan depletion induced by a gelatin-based mixture impairs object memory but not affective behavior and spatial learning in the rat. Behav Brain Res 2004; 151: 53–64.

    Article  CAS  PubMed  Google Scholar 

  84. Brown CM, Fletcher PJ, Coscina DV . Acute amino acid loads that deplete brain serotonin fail to alter behavior. Pharmacol Biochem Behav 1998; 59: 115–121.

    Article  CAS  PubMed  Google Scholar 

  85. Jans L, Korte-Bouws G, Korte S, Blokland A . The effects of acute tryptophan depletion on affective behaviour and cognition in Brown Norway and Sprague Dawley rats. J Psychopharmacol 2008; 24: 605–614.

    Article  PubMed  Google Scholar 

  86. Jans LA, Blokland A . Influence of chronic mild stress on the behavioural effects of acute tryptophan depletion induced by a gelatin-based mixture. Behav Pharmacol 2008; 19: 706–715.

    Article  CAS  PubMed  Google Scholar 

  87. Rutten K, Lieben C, Smits L, Blokland A . The PDE4 inhibitor rolipram reverses object memory impairment induced by acute tryptophan depletion in the rat. Psychopharmacology (Berl) 2007; 192: 275–282.

    Article  CAS  Google Scholar 

  88. van Donkelaar EL, Rutten K, Blokland A, Akkerman S, Steinbusch HW, Prickaerts J . Phosphodiesterase 2 and 5 inhibition attenuates the object memory deficit induced by acute tryptophan depletion. Eur J Pharmacol 2008; 600: 98–104.

    Article  CAS  PubMed  Google Scholar 

  89. Badawy AB . Plasma free tryptophan revisited: what you need to know and do before measuring it. J Psychopharmacol 2010; 24: 809–815.

    Article  CAS  PubMed  Google Scholar 

  90. Oldendorf WH, Szabo J . Amino acid assignment to one of three blood-brain barrier amino acid carriers. Am J Physiol 1976; 230: 94–98.

    Article  CAS  PubMed  Google Scholar 

  91. Crespi F . In vivo voltammetry with micro-biosensors for analysis of neurotransmitter release and metabolism. J Neurosci Methods 1990; 34: 53–65.

    Article  CAS  PubMed  Google Scholar 

  92. Crespi F, Garratt JC, Sleight AJ, Marsden CA . In vivo evidence that 5-hydroxytryptamine (5-HT) neuronal firing and release are not necessarily correlated with 5-HT metabolism. Neuroscience 1990; 35: 139–144.

    Article  CAS  PubMed  Google Scholar 

  93. Westerink BH . Brain microdialysis and its application for the study of animal behaviour. Behav Brain Res 1995; 70: 103–124.

    Article  CAS  PubMed  Google Scholar 

  94. Shannon NJ, Gunnet JW, Moore KE . A comparison of biochemical indices of 5-hydroxytryptaminergic neuronal activity following electrical stimulation of the dorsal raphe nucleus. J Neurochem 1986; 47: 958–965.

    Article  CAS  PubMed  Google Scholar 

  95. Boadle-Biber MC . Regulation of serotonin synthesis. Prog Biophys Mol Biol 1993; 60: 1–15.

    Article  CAS  PubMed  Google Scholar 

  96. Ardis TC, Cahir M, Elliott JJ, Bell R, Reynolds GP, Cooper SJ . Effect of acute tryptophan depletion on noradrenaline and dopamine in the rat brain. J Psychopharmacol 2009; 23: 51–55.

    Article  CAS  PubMed  Google Scholar 

  97. Cahir M, Ardis TC, Elliott JJ, Kelly CB, Reynolds GP, Cooper SJ . Acute tryptophan depletion does not alter central or plasma brain-derived neurotrophic factor in the rat. Eur Neuropsychopharmacol 2008; 18: 317–322.

    Article  CAS  PubMed  Google Scholar 

  98. Fernstrom JD, Hirsch MJ . Brain serotonin synthesis: reduction in corn-malnourished rats. J Neurochem 1977; 28: 877–979.

    Article  CAS  PubMed  Google Scholar 

  99. van der Plasse G, Meerkerk DT, Lieben CK, Blokland A, Feenstra MG . Lack of evidence for reduced prefrontal cortical serotonin and dopamine efflux after acute tryptophan depletion. Psychopharmacology (Berl) 2007; 195: 377–385.

    Article  CAS  Google Scholar 

  100. Bel N, Artigas F . Reduction of serotonergic function in rat brain by tryptophan depletion: effects in control and fluvoxamine-treated rats. J Neurochem 1996; 67: 669–676.

    Article  CAS  PubMed  Google Scholar 

  101. Stancampiano R, Melis F, Sarais L, Cocco S, Cugusi C, Fadda F . Acute administration of a tryptophan-free amino acid mixture decreases 5-HT release in rat hippocampus in vivo. Am J Physiol 1997; 272 (3 Part 2): R991–R994.

    CAS  PubMed  Google Scholar 

  102. Trulson ME . Dietary tryptophan does not alter the function of brain serotonin neurons. Life Sci 1985; 37: 1067–1072.

    Article  CAS  PubMed  Google Scholar 

  103. Young SN, Ervin FR, Pihl RO, Finn P . Biochemical aspects of tryptophan depletion in primates. Psychopharmacology (Berl) 1989; 98: 508–511.

    Article  CAS  Google Scholar 

  104. Lenard NR, Dunn AJ . Mechanisms and significance of the increased brain uptake of tryptophan. Neurochem Res 2005; 30: 1543–1548.

    Article  CAS  PubMed  Google Scholar 

  105. Smith JC, Whitton PS . Nitric oxide modulates N-methyl-D-aspartate-evoked serotonin release in the raphe nuclei and frontal cortex of the freely moving rat. Neurosci Lett 2000; 291: 5–8.

    Article  CAS  PubMed  Google Scholar 

  106. Blokland A, Prickaerts J, Honig W, de Vente J . State-dependent impairment in object recognition after hippocampal NOS inhibition. NeuroReport 1998; 9: 4205–4208.

    Article  CAS  PubMed  Google Scholar 

  107. Dawson VL, Dawson TM . Nitric oxide actions in neurochemistry. Neurochem Int 1996; 29: 97–110.

    Article  CAS  PubMed  Google Scholar 

  108. Prast H, Philippu A . Nitric oxide as modulator of neuronal function. Prog Neurobiol 2001; 64: 51–68.

    Article  CAS  PubMed  Google Scholar 

  109. Kaehler ST, Singewald N, Sinner C, Philippu A . Nitric oxide modulates the release of serotonin in the rat hypothalamus. Brain Res 1999; 835: 346–349.

    Article  CAS  PubMed  Google Scholar 

  110. Prickaerts J, de Vente J, Honig W, Steinbusch HW, Blokland A . cGMP, but not cAMP, in rat hippocampus is involved in early stages of object memory consolidation. Eur J Pharmacol 2002; 436: 83–87.

    Article  CAS  PubMed  Google Scholar 

  111. Lieben CK, Blokland A, Sik A, Sung E, van Nieuwenhuizen P, Schreiber R . The selective 5-HT6 receptor antagonist Ro4368554 restores memory performance in cholinergic and serotonergic models of memory deficiency in the rat. Neuropsychopharmacology 2005; 30: 2169–2179.

    Article  CAS  PubMed  Google Scholar 

  112. Bernabeu R, Schmitz P, Faillace MP, Izquierdo I, Medina JH . Hippocampal cGMP and cAMP are differentially involved in memory processing of inhibitory avoidance learning. NeuroReport 1996; 7: 585–588.

    Article  CAS  PubMed  Google Scholar 

  113. Bernabeu R, Schroder N, Quevedo J, Cammarota M, Izquierdo I, Medina JH . Further evidence for the involvement of a hippocampal cGMP/cGMP-dependent protein kinase cascade in memory consolidation. NeuroReport 1997; 8: 2221–2224.

    Article  CAS  PubMed  Google Scholar 

  114. Rutten K, Prickaerts J, Hendrix M, van der Staay FJ, Sik A, Blokland A . Time-dependent involvement of cAMP and cGMP in consolidation of object memory: studies using selective phosphodiesterase type 2, 4 and 5 inhibitors. Eur J Pharmacol 2007; 558: 107–112.

    Article  CAS  PubMed  Google Scholar 

  115. Blokland A, Schreiber R, Prickaerts J . Improving memory: a role for phosphodiesterases. Curr Pharm Des 2006; 12: 2511–2523.

    Article  CAS  PubMed  Google Scholar 

  116. Domek-Lopacinska K, Strosznajder JB . The effect of selective inhibition of cyclic GMP hydrolyzing phosphodiesterases 2 and 5 on learning and memory processes and nitric oxide synthase activity in brain during aging. Brain Res 2008; 1216: 68–77.

    Article  CAS  PubMed  Google Scholar 

  117. Murad F, Mittal CK, Arnold WP, Katsuki S, Kimura H . Guanylate cyclase: activation by azide, nitro compounds, nitric oxide, and hydroxyl radical and inhibition by hemoglobin and myoglobin. Adv Cyclic Nucleotide Res 1978; 9: 145–158.

    CAS  PubMed  Google Scholar 

  118. Kuschinsky W . Coupling of function, metabolism, and blood flow in the brain. Neurosurg Rev 1991; 14: 163–168.

    Article  CAS  PubMed  Google Scholar 

  119. Sokoloff L . Relationships among local functional activity, energy metabolism, and blood flow in the central nervous system. Fed Proc 1981; 40: 2311–2316.

    CAS  PubMed  Google Scholar 

  120. Drevets WC . Neuroimaging studies of mood disorders. Biol Psychiatry 2000; 48: 813–829.

    Article  CAS  PubMed  Google Scholar 

  121. Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ et al. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999; 46: 1375–1387.

    Article  CAS  PubMed  Google Scholar 

  122. Drevets WC, Ongur D, Price JL . Reduced glucose metabolism in the subgenual prefrontal cortex in unipolar depression. Mol Psychiatry 1998; 3: 190–191.

    Article  CAS  PubMed  Google Scholar 

  123. Drevets WC, Ongur D, Price JL . Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders. Mol Psychiatry 1998; 3: 220–226, 190–191.

    Article  CAS  PubMed  Google Scholar 

  124. Edvinsson L, MacKenzie ET . Amine mechanisms in the cerebral circulation. Pharmacol Rev 1976; 28: 275–348.

    CAS  PubMed  Google Scholar 

  125. Talbot PS, Cooper SJ . Anterior cingulate and subgenual prefrontal blood flow changes following tryptophan depletion in healthy males. Neuropsychopharmacology 2006; 31: 1757–1767.

    Article  CAS  PubMed  Google Scholar 

  126. Dunn RT, Willis MW, Benson BE, Repella JD, Kimbrell TA, Ketter TA et al. Preliminary findings of uncoupling of flow and metabolism in unipolar compared with bipolar affective illness and normal controls. Psychiatry Res 2005; 140: 181–198.

    Article  CAS  PubMed  Google Scholar 

  127. Soares JC, Mann JJ . The functional neuroanatomy of mood disorders. J Psychiatr Res 1997; 31: 393–432.

    Article  CAS  PubMed  Google Scholar 

  128. Kelly PA, Ritchie IM, Arbuthnott GW . Inhibition of neuronal nitric oxide synthase by 7-nitroindazole: effects upon local cerebral blood flow and glucose use in the rat. J Cereb Blood Flow Metab 1995; 15: 766–773.

    Article  CAS  PubMed  Google Scholar 

  129. Kelly PA, Thomas CL, Ritchie IM, Arbuthnott GW . Cerebrovascular autoregulation in response to hypertension induced by NG-nitro-L-arginine methyl ester. Neuroscience 1994; 59: 13–20.

    Article  CAS  PubMed  Google Scholar 

  130. Dundore RL, Clas DM, Wheeler LT, Habeeb PG, Bode DC, Buchholz RA et al. Zaprinast increases cyclic GMP levels in plasma and in aortic tissue of rats. Eur J Pharmacol 1993; 249: 293–297.

    Article  CAS  PubMed  Google Scholar 

  131. Rutten K, Van Donkelaar EL, Ferrington L, Blokland A, Bollen E, Steinbusch HW et al. Phosphodiesterase inhibitors enhance object memory independent of cerebral blood flow and glucose utilization in rats. Neuropsychopharmacology 2009; 34: 1914–1925.

    Article  CAS  PubMed  Google Scholar 

  132. Mattson MP, Maudsley S, Martin B . BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 2004; 27: 589–594.

    Article  CAS  PubMed  Google Scholar 

  133. Ernfors P, Wetmore C, Olson L, Persson H . Identification of cells in rat brain and peripheral tissues expressing mRNA for members of the nerve growth factor family. Neuron 1990; 5: 511–526.

    Article  CAS  PubMed  Google Scholar 

  134. Smith MA, Makino S, Kvetnansky R, Post RM . Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 1995; 15 (3 Part 1): 1768–1777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Kokaia Z, Nawa H, Uchino H, Elmer E, Kokaia M, Carnahan J et al. Regional brain-derived neurotrophic factor mRNA and protein levels following transient forebrain ischemia in the rat. Brain Res Mol Brain Res 1996; 38: 139–144.

    Article  CAS  PubMed  Google Scholar 

  136. Larsson E, Nanobashvili A, Kokaia Z, Lindvall O . Evidence for neuroprotective effects of endogenous brain-derived neurotrophic factor after global forebrain ischemia in rats. J Cereb Blood Flow Metab 1999; 19: 1220–1228.

    Article  CAS  PubMed  Google Scholar 

  137. Lindvall O, Kokaia Z, Bengzon J, Elmer E, Kokaia M . Neurotrophins and brain insults. Trends Neurosci 1994; 17: 490–496.

    Article  CAS  PubMed  Google Scholar 

  138. Lu Y, Christian K, Lu B . BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem 2008; 89: 312–333.

    Article  CAS  PubMed  Google Scholar 

  139. Bliss TV, Collingridge GL . A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993; 361: 31–39.

    Article  CAS  PubMed  Google Scholar 

  140. Lee JL, Everitt BJ, Thomas KL . Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science 2004; 304: 839–843.

    Article  CAS  PubMed  Google Scholar 

  141. Stone TW, Darlington LG . Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov 2002; 1: 609–620.

    Article  CAS  PubMed  Google Scholar 

  142. Botting NP . Chemistry and neurochemistry of the kynurenine pathway of tryptophan metabolism. Chem Soc Rev 1995; 24: 401–412.

    Article  CAS  Google Scholar 

  143. Smith SA, Pogson CI . The metabolism of L-tryptophan by isolated rat liver cells. Effect of albumin binding and amino acid competition on oxidatin of tryptophan by tryptophan 2,3-dioxygenase. Biochem J 1980; 186: 977–996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Moroni F . Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites. Eur J Pharmacol 1999; 375: 87–100.

    Article  CAS  PubMed  Google Scholar 

  145. Hu B, Hissong BD, Carlin JM . Interleukin-1 enhances indoleamine 2,3-dioxygenase activity by increasing specific mRNA expression in human mononuclear phagocytes. J Interferon Cytokine Res 1995; 15: 617–624.

    Article  CAS  PubMed  Google Scholar 

  146. Turner EH, Loftis JM, Blackwell AD . Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan. Pharmacol Ther 2006; 109: 325–338.

    Article  CAS  PubMed  Google Scholar 

  147. Young SN, Leyton M . The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels. Pharmacol Biochem Behav 2002; 71: 857–865.

    Article  CAS  PubMed  Google Scholar 

  148. Stone TW . Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev 1993; 45: 309–379.

    CAS  PubMed  Google Scholar 

  149. Morris RG . Long-term potentiation and memory. Philos Trans R Soc Lond B Biol Sci 2003; 358: 643–647.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Morris RG, Davis S, Butcher SP . Hippocampal synaptic plasticity and NMDA receptors: a role in information storage? Philos Trans R Soc Lond B Biol Sci 1990; 329: 187–204.

    Article  CAS  PubMed  Google Scholar 

  151. Morris RG, Anderson E, Lynch GS, Baudry M . Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 1986; 319: 774–776.

    Article  CAS  PubMed  Google Scholar 

  152. Lipton SA . Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov 2006; 5: 160–170.

    Article  CAS  PubMed  Google Scholar 

  153. Stone TW, Perkins MN . Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol 1981; 72: 411–412.

    Article  CAS  PubMed  Google Scholar 

  154. Stone TW, Forrest CM, Mackay GM, Stoy N, Darlington LG . Tryptophan, adenosine, neurodegeneration and neuroprotection. Metab Brain Dis 2007; 22: 337–352.

    Article  CAS  PubMed  Google Scholar 

  155. Stone TW . Endogenous neurotoxins from tryptophan. Toxicon 2001; 39: 61–73.

    Article  CAS  PubMed  Google Scholar 

  156. Schwarcz R, Whetsell Jr WO, Mangano RM . Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science 1983; 219: 316–318.

    Article  CAS  PubMed  Google Scholar 

  157. de Kloet ER, Joels M, Holsboer F . Stress and the brain: from adaptation to disease. Nat Rev Neurosci 2005; 6: 463–475.

    Article  CAS  PubMed  Google Scholar 

  158. van Praag HM . Can stress cause depression? Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 891–907.

    Article  CAS  PubMed  Google Scholar 

  159. Curzon G, Joseph MH, Knott PJ . Effects of immobilization and food deprivation on rat brain tryptophan metabolism. J Neurochem 1972; 19: 1967–1974.

    Article  CAS  PubMed  Google Scholar 

  160. Chamas FM, Underwood MD, Arango V, Serova L, Kassir SA, Mann JJ et al. Immobilization stress elevates tryptophan hydroxylase mRNA and protein in the rat raphe nuclei. Biol Psychiatry 2004; 55: 278–283.

    Article  CAS  PubMed  Google Scholar 

  161. Nakahara D, Nakamura M . Differential effect of immobilization stress on in vivo synthesis rate of monoamines in medial prefrontal cortex and nucleus accumbens of conscious rats. Synapse 1999; 32: 238–242.

    Article  CAS  PubMed  Google Scholar 

  162. Jahng JW, Kim JG, Kim HJ, Kim BT, Kang DW, Lee JH . Chronic food restriction in young rats results in depression- and anxiety-like behaviors with decreased expression of serotonin reuptake transporter. Brain Res 2007; 1150: 100–107.

    Article  CAS  PubMed  Google Scholar 

  163. Chaouloff F . Physiopharmacological interactions between stress hormones and central serotonergic systems. Brain Res Brain Res Rev 1993; 18: 1–32.

    Article  CAS  PubMed  Google Scholar 

  164. McMenamy RH . Binding of indole analogues to human serum albumin. Effects of fatty acids. J Biol Chem 1965; 240: 4235–4243.

    CAS  PubMed  Google Scholar 

  165. van Donkelaar EL, Blokland A, Lieben CK, Kenis G, Ferrington L, Kelly PA et al. Acute tryptophan depletion in C57BL/6 mice does not induce central serotonin reduction or affective behavioural changes. Neurochem Int 2010; 56: 21–34.

    Article  CAS  PubMed  Google Scholar 

  166. King MV, Marsden CA, Fone KC . A role for the 5-HT(1A), 5-HT(4) and 5-HT(6) receptors in learning and memory. Trends Pharmacol Sci 2008; 29: 482–492.

    Article  CAS  PubMed  Google Scholar 

  167. Laaris N, Haj-Dahmane S, Hamon M, Lanfumey L . Glucocorticoid receptor-mediated inhibition by corticosterone of 5-HT1A autoreceptor functioning in the rat dorsal raphe nucleus. Neuropharmacology 1995; 34: 1201–1210.

    Article  CAS  PubMed  Google Scholar 

  168. Duman RS . Novel therapeutic approaches beyond the serotonin receptor. Biol Psychiatry 1998; 44: 324–335.

    Article  CAS  PubMed  Google Scholar 

  169. Jans LA, Lieben CK, Smits LT, Blokland A . Pharmacokinetics of acute tryptophan depletion using a gelatin-based protein in male and female Wistar rats. Amino Acids 2009; 37: 349–357.

    Article  CAS  PubMed  Google Scholar 

  170. van Donkelaar EL, Kelly PA, Dawson N, Blokland A, Prickaerts J, Steinbusch HW et al. Acute tryptophan depletion potentiates 3,4-methylenedioxymethamphetamine-induced cerebrovascular hyperperfusion in adult male Wistar rats. J Neurosci Res 2010; 88: 1557–1568.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands

    E L van Donkelaar, H W M Steinbusch & J Prickaerts

  2. Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands

    A Blokland

  3. Cerebrovascular Research Laboratory, Centre for Cognitive and Neural Systems, University of Edinburgh, Edinburgh, UK

    L Ferrington & P A T Kelly

Authors
  1. E L van Donkelaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Blokland
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Ferrington
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P A T Kelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H W M Steinbusch
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Prickaerts
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E L van Donkelaar.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Donkelaar, E., Blokland, A., Ferrington, L. et al. Mechanism of acute tryptophan depletion: is it only serotonin?. Mol Psychiatry 16, 695–713 (2011). https://doi.org/10.1038/mp.2011.9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2011.9

Keywords

This article is cited by

Search

Advanced search

Quick links