Psychopharmacology

, Volume 174, Issue 1, pp 32–38

The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia

Review

Abstract

Numerous clinical studies demonstrate that subanaesthetic doses of dissociative anaesthetics, which are non-competitive antagonists at the NMDA receptor, replicate in normal subjects the cognitive impairments, negative symptoms and brain functional abnormalities of schizophrenia. Post-mortem and genetic studies have identified several abnormalities associated with schizophrenia that would interfere with the activation of the glycine modulatory site on the NMDA receptor. Placebo controlled clinical trials with agents that directly or indirectly activate the glycine modulatory site consistently reduce negative symptoms and frequently improve cognition in patients with chronic schizophrenia, who are receiving concurrent typical antipsychotics. Thus, there is convincing evidence that the glycine modulatory site on the NMDA receptor is a valid therapeutic target for improving cognition and associated negative symptoms in schizophrenia.

Keywords

NMDA receptor Schizophrenia Glycine modulatory site Glycine -Serine -Cycloserine Negative symptoms 

References

  1. Avila MT, Weller MA, Lahti AC, Tamminga CA, Thaker CK (2002) Effects of ketamine on leading saccades during smooth-pursuit eye movements may implicate cerebellar dysfunction in schizophrenia. Am J Psychiatry 159:1490–1496CrossRefPubMedGoogle Scholar
  2. Berger UV, Hediger MA (1998) Comparative analysis of glutamate transporter expression in rat brain using differential double in situ hybridization. Anat Embryol 198:13–30CrossRefPubMedGoogle Scholar
  3. Berger AJ, Dieudonne S, Ascher P (1998) Glycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses. J Neurophysiol 80:3336–3340PubMedGoogle Scholar
  4. Berger UV, Luthi-Carter R, Passani La, Elkabes S, Black I, Konradi C, Coyle JT (1999) Glutamate carboxypeptidase II is expressed by astrocytes in the adult rat nervous system. J Comp Neurol 415:52–64CrossRefPubMedGoogle Scholar
  5. Bergeron R, Meyer TM, Coyle JT, Greene RW (1998) Modulation of N-methyl-d-aspartate receptor function by glycine transport. Proc Natl Acad Sci USA 95:15730–15734CrossRefPubMedGoogle Scholar
  6. Buonanno A, Fischbach GD (2001) Neuregulin and ErbB Receptor signaling pathways in the nervous system. Curr Opin Neurobiol 11:287–296CrossRefPubMedGoogle Scholar
  7. Carone FA, Ganote CE (1975) d-Serine nephrotoxicity. The nature of proteinuria, glucosuria, and aminoaciduria in acute tubular necrosis. Arch Pathol 99:658–662PubMedGoogle Scholar
  8. Casella NG, Macciardi F, Cavallini C, Smeraldi E (1994) d-Cycloserine adjuvant therapy to conventional neuroleptic treatment in schizophrenia: an open-label study. J Neural Transm [Gen Sect] 95:105–111Google Scholar
  9. Chen L, Muhlhauser M, Yang CR (2003) Glycine transporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. J Neurophysiol 89:691–703PubMedGoogle Scholar
  10. Chumakov I, Blumenfeld M, Guerassimenko O, et al (2002) Genetic and physiological data implicating the new human gene G72 and the gene for d-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 99:13675–13680CrossRefPubMedGoogle Scholar
  11. Cook SP, Galve-Roperh I, Martinez del Pozo A, Rodriguez-Crespo I (2002) Direct calcium binding results in activation of brain serine racemase. J Biol Chem 277:27782–27792CrossRefPubMedGoogle Scholar
  12. Coyle JT, Tsai G, Goff DC (2002) Ionotropic glutamate receptors as therapeutic targets in schizophrenia. Curr Drug Target CNS Neurol Disord 1:183–189PubMedGoogle Scholar
  13. DeLisi LE (1999) Defining the course of brain structural change and plasticity in schizophrenia. Psychiatry Res 92:1–9CrossRefPubMedGoogle Scholar
  14. Evins AE, Firzgerald SM, Wine L, Rosselli R, Goff DC (2000) Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry 157:826–828CrossRefPubMedGoogle Scholar
  15. Goff D, Coyle JT (2001) The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 158:1367–1377PubMedGoogle Scholar
  16. Goff DC, Tsai GC, Monoach DS, Coyle JT (1995) Dose-finding trial of d-cycloserine added to neuroleptics for negative symptoms in schizophrenia. Am J Psychiatry 152:1213–1215PubMedGoogle Scholar
  17. Goff DC, Tsai G, Monach DS, Flood J, Darby DG, Coyle JT (1996) d-Cycloserine added to clozapine for patients with schizophrenia. Am J Psychiatry 153:1628–1630PubMedGoogle Scholar
  18. Goff DC, Henderson DC, Evins AE, Amico E (1999a) A placebo-controlled crossover trial of d-cycloserine added to clozapine in patients with schizophrenia. Biol Psychiatry 45:512–514CrossRefPubMedGoogle Scholar
  19. Goff DC, Tsai G, Levitt L, Amico E, Monach D, Schoenfeld D, Hayden DL, McCarley R, Coyle JT (1999b) A placebo-controlled trial of d-cycloserine added to conventional neuroleptics in patients with schizophrenia. Arch Gen Psychiatry 56:21–27PubMedGoogle Scholar
  20. Grimwood S, Le Bourdelles B, Atack JR, Barton C, Cockett W, Cook SM, Gilbert E, Hutson PH, McKernan RM, Myers J, Ragan CI, Wingrove PB, Whiting PJ (1996) Generation and characterization of stable cell lines expressing recombinant human N-methyl-d-aspartate receptor subtypes. J Neurochem 66:2239–2247PubMedGoogle Scholar
  21. Hakak Y, Walker JR, Li C, Wong WH, Davis KL, Buxbaum JD, Haroutunian V, Fienberg AA (2001) Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA 98:4746–4751PubMedGoogle Scholar
  22. Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, Nakazato M, Kumakiri C, Okada S, Hasegawa H, Imai K, Iyo M (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 56:21–27Google Scholar
  23. Herndon HJ, Godfrey FM, Brown AM, Coulton S, Evans JR, Cairns WJ (2001) Pharmacological assessment of the role of the glycine transporter GlyT-1 in mediating high-affinity glycine uptake by rat cerebral cortex and cerebellum synaptosomes. Neuropharmacology 41:88–96CrossRefPubMedGoogle Scholar
  24. Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Horowitz A, Kelly D (1996) Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia. Br J Psychiatry 169:610–617PubMedGoogle Scholar
  25. Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, Lichtenstein M (1999) Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 56:29–36PubMedGoogle Scholar
  26. Itil T, Keskiner A, Kiremitci N, Holden JMC (1967) Effect of phencyclidine in chronic schizophrenics. Can Psychiatr Assoc J 12:209–212PubMedGoogle Scholar
  27. Jardemark KE, Liang X, Arvanov V, Wang RY(2000) Subchronic treatment with either clozapine, olanzapine or haloperidol produces a hyposensitive response of the rat cortical cells to N-methyl-d-aspartate. Neuroscience 100:1–9Google Scholar
  28. Javitt DC, Zukin SR (1989) Interaction of [3H]MK-801 with multiple states of the N-methyl-d-aspartate receptor complex of rat brain. Proc Natl Acad Sci USA 86:740–744PubMedGoogle Scholar
  29. Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308PubMedGoogle Scholar
  30. Javitt DC, Zylberman I, Zukin SR, Heresco-Levy U, Lindenmayer JP (1994) Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry 151:1234–1236PubMedGoogle Scholar
  31. Javitt DC, Balla A, Sershen H, Lajtha A (1999) A.E. Bennett Research Award. Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors. Biol Psychiatry 45:668–679PubMedGoogle Scholar
  32. Kegeles LS, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann JJ, Van Heertum RL, Cooper TB, Carlsson A, Laruelle M (2000) Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry 48:627–640PubMedGoogle Scholar
  33. Kinney GG, Sur C, Burno M, Mallorga PJ, Williams JB, Figueroa DJ, Wittmann M, Lemaire W, Conn PJ (2003) The glycine transporter type 1 inhibitor N-[3-(4’-fluorophenyl)-3(4’-phenylphenoxy)propyl]sarcosine potentiates NMDA receptor-mediated responses in vivo and produces an antipsychotic profile in rodent behavior. J Neurosci 23:7586–7591PubMedGoogle Scholar
  34. Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B (1994) Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes. Mol Pharmacol 45:608–617PubMedGoogle Scholar
  35. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MBJ, Charney DS (1994) Subanaesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214PubMedGoogle Scholar
  36. Lea PM 4th, Wroblewska B, Sarvey JM, Neale JH (2001) beta-NAAG rescues LTP from blockade by NAAG in rat dentate gyrus via the type 3 metabotropic glutamate receptor. J Neurophysiol 85:1097–1106PubMedGoogle Scholar
  37. Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R (1959) Study of a new schizophrenomimetic drug—sernyl. Arch Neurol Psychiatry 81:363–369Google Scholar
  38. Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, Breier A (1997) Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17:141–150PubMedGoogle Scholar
  39. Marti SB, Cichon S. Propping P, Nothen M (2002) Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population. Am J Med Genet 114:46–50CrossRefPubMedGoogle Scholar
  40. Meltzer HY (1997) Treatment-resistant schizophrenia—the role of clozapine. Curr Med Res Opin 14:1–20PubMedGoogle Scholar
  41. Mothet J-P, Parent AT, Wolosker H, et al (2000) d-Serine is an endogenous ligand for the glycine site of the N-methyl-d-aspartate receptor. Proc Natl Acad Sci USA 97:4926–4931CrossRefPubMedGoogle Scholar
  42. Newcomer J, Farber N, Jevtovic-Todorovic V, Selke G, Melson A, Hershey T, Craft S, Olney J (1999) Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20:106–118PubMedGoogle Scholar
  43. Olney JW (2003) Excitotoxicity, apoptosis and neuropsychiatric disorders. Curr Opin Pharmacol 3:101–109CrossRefPubMedGoogle Scholar
  44. Potkin SG, Jin Y, Bunney BG, Costa J, Gulasekaram B (1999) Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia. Am J Psychiatry 156:145–147PubMedGoogle Scholar
  45. Schwarcz R, Rassoulpour A, Wu HQ, Medoff D, Tamminga CA, Roberts RC (2001) Increased cortical kynurenate content in schizophrenia. Biol Psychiatry 50:521–530CrossRefPubMedGoogle Scholar
  46. Sheinin A, Shavit S, Benveniste M (2001) Subunit specificity and mechanism of action of NMDA partial agonist d-cycloserine. Neuropharmacology 41:151–158CrossRefPubMedGoogle Scholar
  47. Snyder SH (1981) Dopamine receptors, neuroleptics, and schizophrenia. Am J Psychiatry 138:460–464PubMedGoogle Scholar
  48. Stefansson H, Sigurdsson E, Steinhorsdottir V, et al (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892CrossRefPubMedGoogle Scholar
  49. Tsai G, Passani LA, Slusher BS, Carter R, Baer L, Kleinman JE, Coyle JT (1995) Abnormal excitatory neurotransmitter metabolism in schizophrenic brains. Arch Gen Psychiatry 52:829–836PubMedGoogle Scholar
  50. Tsai G, Yang P, Chung L-C, Lange N, Coyle JT (1998) d-Serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 44:1081–1089CrossRefPubMedGoogle Scholar
  51. Tsai GE, Yang P, Chung LC, Tsai IC, Tsai CW, Coyle JT (1999) d-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry 156:1822–1825PubMedGoogle Scholar
  52. Tsai G, Lane H, Young PJ, Lane N, Chong M (2003) Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry (in press)Google Scholar
  53. Tsien JZ (2000) Linking Hebb’s coincidence-detection to memory formation. Curr Opin Neurobiol 10:266–273CrossRefPubMedGoogle Scholar
  54. Umbricht D, Koller R, Vollenweider FX, Schmid L (2002) Mismatch negativity predicts psychotic experiences induced by NMDA receptor antagonist in healthy volunteers. Biol Psychiatry 51:400–406CrossRefPubMedGoogle Scholar
  55. Van Berckel BN, Hijman R, van der Linden JA, Westenberg HG, van Ree JM, Kahn RS (1996) Efficacy and tolerance of d-cycloserine in drug-free schizophrenic patients. Biol Psychiatry 40:1298–1300CrossRefPubMedGoogle Scholar
  56. Verma A, Moghaddam B (1996) NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine. J Neurosci 16:373–379PubMedGoogle Scholar
  57. Vollenweider FX, Leenders KL, Scharfetter C, Antonini A, Maguire P, Missimer J, Angst J (1997) Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F] fluorodeoxyglucose (FDG). Eur Neuropsychopharmacol 7:9–24PubMedGoogle Scholar
  58. Wroblewska B, Wroblewski JT, Pshenichkin S, Surin A, Sullivan SE, Neale JH (1997) N-Acetylaspartylglutamate selectively activates mGluR3 receptors in transfected cells. J Neurochem 69:174–181PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  1. 1.Department of Psychiatry, Harvard Medical SchoolMcLean HospitalBelmontUSA

Personalised recommendations