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Amino Acids in Schizophrenia – Glycine, Serine and Arginine

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Handbook of Schizophrenia Spectrum Disorders, Volume I

Abstract

In recent years, there has been increased interest in the possible role of amino acids in the etiology and pharmacotherapy of schizophrenia. Much of this research has focused on glutamate and γ-aminobutyric acid (GABA), and these are the subjects of other chapters in this book. However, there have also been interesting findings reported with glycine, serine (particularly D-serine) and arginine, and this chapter provides a brief overview of those findings. Glycine and D-serine are coagonists at the NMDA glutamate receptor and lower plasma levels of these two amino acids have been reported in schizophrenia compared to controls. Combinations of glycine with antipsychotics or glycine transport inhibitors have been reported to be useful in treatment of schizophrenia, and increased glycine serum levels have been reported in schizophrenia patients responsive to antipsychotics. Behavioural studies in mutant mice in which D-serine levels are altered by manipulating catabolic or anabolic enzymes suggest that inhibitors of D-amino acid oxidase (DAO), particularly in combination with D-serine, may represent a useful future therapeutic approach to the treatment of schizophrenia. Arginine, a precursor to nitric oxide (NO) is also of interest in schizophrenia, although at present there is evidence for both hypo- and hyperfunction of this amino acid in schizophrenia and further clarification is required.

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Abbreviations

DA:

Dopamine

DAO:

D-amino acid oxidase

fMRI:

functional magnetic resonance imaging

GABA:

γ-Aminobutyric acid

GTI:

Glycine transport inhibitor

HPLC:

High performance liquid chromatography

5-HT:

5-Hydroxytryptamine

L-NAME:

Nitro-L-arginine methyl ester

MWM:

Morris water maze

NMDA:

N-methyl-D-aspartic acid

NMDAR:

NMDA receptor

NO:

Nitric oxide

PCP:

Phencyclidine

PFC:

Prefrontal cortex

PLP:

Pyridoxal 5-phosphate

PPI:

Pre-pulse inhibition

References

  1. Baumeister AA, Francis JL (2002) Historical development of the dopamine hypothesis of schizophrenia. J Hist Neurosci 11:265–277

    Article  PubMed  Google Scholar 

  2. Davis KL, Kahn RS, Ko G et al (1991) Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 148:1474–1486

    CAS  PubMed  Google Scholar 

  3. Seeman P, Schwarz J, Chen JF et al (2006) Psychosis pathways converge via D2high dopamine receptors. Synapse 60:319–346

    Article  CAS  PubMed  Google Scholar 

  4. Seeman P (2008) All psychotic roads lead to increased dopamine D2High receptors: a perspective. Clin Schizophr Relat Psychoses 1:351–355

    Article  Google Scholar 

  5. Goff DC, Coyle JT (2001) The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 158:1367–1377

    Article  CAS  PubMed  Google Scholar 

  6. Krystal JH, Perry EB Jr, Gueorguieva R et al (2005) Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function. Arch Gen Psychiatry 62:985–994

    Article  CAS  PubMed  Google Scholar 

  7. Gordon JA (2010) Testing the glutamate hypothesis of schizophrenia. Nat Neurosci 13:2–4

    Article  CAS  PubMed  Google Scholar 

  8. Coyle JT, Tsai G, Goff D (2003) Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann NY Acad Sci 1003:318–327

    Article  CAS  PubMed  Google Scholar 

  9. Meador-Woodruff JH, Healy DJ (2000) Glutamate receptor expression in schizophrenic brain. Brain Res Brain Res Rev 31:288–294

    Article  CAS  PubMed  Google Scholar 

  10. Dursun SM, Deakin JF (2001) Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study. J Psychopharmacol 15:297–301

    Article  CAS  PubMed  Google Scholar 

  11. Blum BP, Mann JJ (2002) The GABAergic system in schizophrenia. Int J Neuropsychopharmacol 5:159–179

    Article  CAS  PubMed  Google Scholar 

  12. Coyle JT (2004) A glutamate connection in schizophrenia: which is the proximate cause? Biochem Pharmacol 68:1507–1514

    Article  CAS  PubMed  Google Scholar 

  13. Guidotti A, Auta J, Davis JM et al (2005) GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon. Psychopharmacology (Berl) 180:191–205

    Article  CAS  Google Scholar 

  14. Labrie V, Lipina T, Roder JC (2008) Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia. Psychopharmacology 200:217–230

    Article  CAS  PubMed  Google Scholar 

  15. Neeman G, Blanaru M, Bloch B et al (2005) Relation of plasma glycine, serine, and homocysteine levels to schizophrenia symptoms and medication type. Am J Psychiatry 162:1738–1740

    Article  PubMed  Google Scholar 

  16. Sumiyoshi T, Anil AE, Jin D et al (2004) Plasma glycine and serine levels in schizophrenia compared to normal controls and major depression: relation to negative symptoms. Int J Neuropsychopharmacol 7:1–8

    Article  CAS  PubMed  Google Scholar 

  17. Hons J, Zirko R, Ulrychova M et al (2010) Glycine serum level in schizophrenia: relation to negative symptoms. Psychiatry Res 176:103–108

    Article  CAS  PubMed  Google Scholar 

  18. Sumiyoshi T, Jin D, Jayathilake K et al (2005) Prediction of the ability of clozapine to treat negative symptoms from plasma glycine and serine levels in schizophrenia. Int J Neuropsychopharmacol 8:451–455

    Article  CAS  PubMed  Google Scholar 

  19. Cunha M, Dursun S, Hial V et al (in press) Serum glutamate, serine, and glycine in treatment-responsive and treatment-resistant schizophrenia: can plasma amino acids predict treatment-resistance? J Psychopharmacol

    Google Scholar 

  20. Kaufman MJ, Prescot AP, Ongur D et al (2009) Oral glycine administration increases brain glycine/creatine ratios in men: a proton magnetic resonance spectroscopy study. Psychiatry Res 173:143–149

    Article  CAS  PubMed  Google Scholar 

  21. Heresco-Levy U, Ermilov M, Lichtenberg P et al (2004) High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry 55:165–171

    Article  CAS  PubMed  Google Scholar 

  22. Yang SY, Hong CJ, Huang YH et al (2010) The effects of glycine transporter I inhibitor, N-methylglycine (sarcosine), on ketamine-induced alterations in sensorimotor gating and regional brain c-Fos expression in rats. Neurosci Lett 469:127–130

    Article  CAS  PubMed  Google Scholar 

  23. Boulay D, Pichat P, Dargazanli G et al (2008) Characterization of SSR103800, a selective inhibitor of the glycine transporter-1 in models predictive of therapeutic activity in schizophrenia. Pharmacol Biochem Behav 91:47–58

    Article  CAS  PubMed  Google Scholar 

  24. Tsai GE, Lin PY (2010) Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis. Curr Pharm Des 16:522–537

    Article  CAS  PubMed  Google Scholar 

  25. Yang CR, Svensson KA (2008) Allosteric modulation of NMDA receptor via elevation of brain glycine and D-serine: the therapeutic potentials for schizophrenia. Pharmacol Ther 120:317–332

    Article  CAS  PubMed  Google Scholar 

  26. Boulay D, Bergis O, Avenet P et al (2010) The glycine transporter-I inhibitor SSRI03800 displays a selective and specific antipsychotic-like profile in normal and transgenic mice. Neuropsychopharmacology 35:416–427

    Article  CAS  PubMed  Google Scholar 

  27. Kantrowitz JT, Javitt DC (2010) N-methyl-D-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull. doi:10.1016/j.brainresbull/2010.04.006

    Google Scholar 

  28. Panizzutti R, Rausch M, Zurbrugg S et al (2005) The pharmacological stimulation of NMDA receptors via co-agonist site: an fMRI study in the rat brain. Neurosci Lett 380:111–115

    Article  CAS  PubMed  Google Scholar 

  29. Waziri R, Baruah S, Sherman AD (1993) Abnormal serine-glycine metabolism in the brains of schizophrenics. Schizophr Res 8:233–243

    Article  CAS  PubMed  Google Scholar 

  30. Waziri R, Mott J, Wilcox J (1985) Differentiation of psychotic from nonpsychotic depression by a biological marker. J Affect Disord 9:175–180

    Article  CAS  PubMed  Google Scholar 

  31. Macciardi F, Lucca A, Catalano M et al (1990) Amino acid patterns in schizophrenia: some new findings. Psychiatry Res 32:63–70

    Article  CAS  PubMed  Google Scholar 

  32. Fekkes D, Pepplinkhuizen L, Verheij R et al (1994) Abnormal plasma levels of serine, methionine, and taurine in transient acute polymorphic psychosis. Psychiatry Res 51:11–18

    Article  CAS  PubMed  Google Scholar 

  33. Baruah S, Waziri R, Sherman A (1993) Neuroleptic effects on serine and glycine metabolism. Biol Psychiatry 34:544–550

    Article  CAS  PubMed  Google Scholar 

  34. Altamura CA, Mauri MC, Ferrara A et al (1993) Plasma and platelet excitatory amino acids in psychiatric disorders. Am J Psychiatry 150:1731–1733

    Google Scholar 

  35. Neeman G, Blanaru M, Bloch B et al (2005) Relation of plasma glycine, serine, and homocysteine levels to schizophrenia symptoms and medication type. Am J Psychiatry 162:1738–1740

    Article  Google Scholar 

  36. Hashimoto K, Fukushima T, Shimizu E et al (2003) Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry 60:572–576

    Article  CAS  PubMed  Google Scholar 

  37. Ohnuma T, Sakai Y, Maeshima H et al (2008) Changes in plasma glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP). Prog Neuropsychopharmacol Biol Psychiatry 32:1905–1912

    Article  Google Scholar 

  38. Labrie V, Fukumura R, Rastogi A et al (2009) Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model. Hum Mol Gen 18:3227–3243

    Article  CAS  PubMed  Google Scholar 

  39. Duffy S, Labrie V, Roder J (2008) D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning. Neuropsychopharmacology 33:1004–1018

    Article  CAS  PubMed  Google Scholar 

  40. Heresco-Levy U, Javitt DC, Ebstein R et al (2005) D-Serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry 57:577–585

    Article  CAS  PubMed  Google Scholar 

  41. Lane HY, Chang YC, Liu YC et al (2005) Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia. Arch Gen Psychiatry 62:1196–1204

    Article  CAS  PubMed  Google Scholar 

  42. Tsai GE, Yang P, Chung LC et al (1999) D-Serine added to clozapine for the treatment of schizophrenia. Am J Psychaitry 156:1822–1825

    Google Scholar 

  43. Labrie V, Wang W, Barger SW et al (2010) Genetic loss of D-amino acid oxidase activity reverses schizophrenia-like phenotypes in mice. Genes Brain Behav 9:11–25

    Article  CAS  PubMed  Google Scholar 

  44. Williams M (2009) Commentary: genome-based CNS drug discovery: D-amino acid oxidase (DAAO) as a novel target for antipsychotic medications: progress and challenges. Biochem Pharmacol 78:1360–1365

    Article  CAS  PubMed  Google Scholar 

  45. Laura C, Gianluca M, Luisa B et al (2010) Effect of ligand binding on human D-amino acid oxidase: implications for the development of new drugs for schizophrenia treatment. Protein Sci 19:1500–1512

    Article  Google Scholar 

  46. Hashimoto K, Fujita Y, Horio M et al (2009) Co-administration of a D-amino acid oxidase inhibitor potentiates the efficacy of D-serine in attenuating prepulse inhibition deficits after administration of dizocilpine. Biol Psychiatry 65:1103–1106

    Article  CAS  PubMed  Google Scholar 

  47. Iwana S, Kawazoe T, Park HK et al (2008) Chlorpromazine oligomer is a potentially active substance that inhibits human D-amino acid oxidase, product of a susceptibility gene for schizophrenia. J Enzyme Inhib Med Chem 23:901–911

    Article  CAS  PubMed  Google Scholar 

  48. Abou El-Magd RM, Park HK, Kawazoe T et al (2010) The effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia. J Psychopharmacol 24:1055–1067

    Article  CAS  PubMed  Google Scholar 

  49. Hashimoto K (2010) Comments on ‘the effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia’. J Psychopharmacol 24:1133–1134

    Article  PubMed  Google Scholar 

  50. Schell MJ (2004) The N-methyl-D-aspartate glycine site and D-serine metabolism: an evolutionary perspective. Philos T Roy Soc B 359:943–964

    Article  CAS  Google Scholar 

  51. Bernstein HG, Bogerts B, Keilhoff G (2005) The many faces of nitric oxide in schizophrenia: a review. Schizophr Res 78:69–86

    PubMed  Google Scholar 

  52. Akyol O, Zoroglu SS, Armutcu F et al (2004) Nitric oxide as a physiopathological factor in neuropsychiatric disorders. In Vivo 18:377–390

    CAS  PubMed  Google Scholar 

  53. MacKay M, Cetin M, Baker G, Dursun S (2010) Modulation of central nitric oxide as a therapeutic strategy for schizophrenia. Bull Clin Psychopharmacol 20:115–119

    CAS  Google Scholar 

  54. Palsson E, Finnerty N, Fejgin K et al (2009) Increased cortical nitric oxide release after phencyclidine administration. Synapse 63:1083–1088

    Article  CAS  PubMed  Google Scholar 

  55. Wass C, Svensson L, Fejgin K et al (2008) Nitric oxide synthase inhibition attenuates phencyclidine-induced disruption of cognitive flexibility. Pharmacol Biochem Behav 89:352–359

    Article  CAS  PubMed  Google Scholar 

  56. Fejgin K, Palsson E, Wass C et al (2008) Nitric oxide signaling in the medial prefrontal cortex is involved in the biochemical and behavioral effects of phencyclidine. Neuropsychopharmacology 33:1874–1883

    Article  Google Scholar 

  57. Palsson E, Fejgin K, Wass C et al (2007) The amino acid L-lysine blocks the disruptive effect of phencyclidine on prepulse inhibition in mice. Psychopharmacology (Berl) 192:9–15

    Article  CAS  Google Scholar 

  58. Bujas-Bobanovic M, Robertson HA, Dursun SM (2000) Effects of nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester on phencyclidine-induced effects in rats. Eur J Pharmacol 409:57–65

    Article  CAS  PubMed  Google Scholar 

  59. Bujas-Bobanovic M, Bird DC, Robertson HA et al (2000) Blockade of phencyclidine-induced effects by a nitric oxide donor. Br J Pharmacol 130:1005–1012

    Article  CAS  PubMed  Google Scholar 

  60. Pitsikas N, Zisopoulou S, Sakellaridis N (2006) Nitric oxide donor molsidomine attenuates psychotomimetic effects of the NMDA receptor antagonist MK-801. J Neurosci Res 84:299–305

    Article  CAS  PubMed  Google Scholar 

  61. Xing G, Chavko M, Zhang LX et al (2002) Decreased calcium-dependent constitutive nitric oxide synthase (cNOS) activity in prefrontal cortex in schizophrenia and depression. Schizophr Res 58:21–30

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to the following for funding: Canadian Institutes of Health Research (CIHR); Faculty of Medicine and Dentistry, University of Alberta; Alberta Hospital Edmonton; and the Canada Research Chairs program. The expert secretarial assistance of Sara Tomlinson is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Neurochemical Research Unit and Bebensee Schizophrenia Research Unit, Department of Psychiatry, University of Alberta, Edmonton, AB, Canada, T6G 2G3

    Glen B. Baker

  2. National Science and Technology Institute for Translational Medicine, Ribeirão Preto, SP, Brazil

    Jaime E.C. Hallak & Serdar M. Dursun

  3. Department of Neuroscience and Behavioral Sciences, Ribeirao Preto School of Medicine, University of Sao Paulo (USP), Ribeirão Preto, SP, Brazil

    Jaime E.C. Hallak

  4. Neurochemical Research Unit and Bebensee Schizophrenia Research Unit, Department of Psychiatry, University of Alberta, Edmonton, AB, Canada

    Alexandria F. Dilullo, Lisa Burback & Serdar M. Dursun

Authors
  1. Glen B. Baker
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  2. Jaime E.C. Hallak
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  3. Alexandria F. Dilullo
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  4. Lisa Burback
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  5. Serdar M. Dursun
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Corresponding author

Correspondence to Glen B. Baker .

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Editors and Affiliations

  1. Sha'ar Menashe Mental Health Center, Hadera, 38814, Israel

    Michael S. Ritsner

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Baker, G.B., Hallak, J.E., Dilullo, A.F., Burback, L., Dursun, S.M. (2011). Amino Acids in Schizophrenia – Glycine, Serine and Arginine. In: Ritsner, M. (eds) Handbook of Schizophrenia Spectrum Disorders, Volume I. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0837-2_11

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