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

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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.

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References

  • 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 159:1490–1496

    Article  PubMed  Google Scholar 

  • Berger UV, Hediger MA (1998) Comparative analysis of glutamate transporter expression in rat brain using differential double in situ hybridization. Anat Embryol 198:13–30

    Article  CAS  PubMed  Google Scholar 

  • Berger AJ, Dieudonne S, Ascher P (1998) Glycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses. J Neurophysiol 80:3336–3340

    CAS  PubMed  Google Scholar 

  • 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 415:52–64

    Article  CAS  PubMed  Google Scholar 

  • 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 95:15730–15734

    Article  CAS  PubMed  Google Scholar 

  • Buonanno A, Fischbach GD (2001) Neuregulin and ErbB Receptor signaling pathways in the nervous system. Curr Opin Neurobiol 11:287–296

    Article  CAS  PubMed  Google Scholar 

  • Carone FA, Ganote CE (1975) d-Serine nephrotoxicity. The nature of proteinuria, glucosuria, and aminoaciduria in acute tubular necrosis. Arch Pathol 99:658–662

    CAS  PubMed  Google Scholar 

  • 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] 95:105–111

    Google Scholar 

  • 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 89:691–703

    CAS  PubMed  Google Scholar 

  • 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 99:13675–13680

    Article  CAS  PubMed  Google Scholar 

  • 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 277:27782–27792

    Article  CAS  PubMed  Google Scholar 

  • Coyle JT, Tsai G, Goff DC (2002) Ionotropic glutamate receptors as therapeutic targets in schizophrenia. Curr Drug Target CNS Neurol Disord 1:183–189

    CAS  PubMed  Google Scholar 

  • DeLisi LE (1999) Defining the course of brain structural change and plasticity in schizophrenia. Psychiatry Res 92:1–9

    Article  CAS  PubMed  Google Scholar 

  • Evins AE, Firzgerald SM, Wine L, Rosselli R, Goff DC (2000) Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry 157:826–828

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • 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 152:1213–1215

    CAS  PubMed  Google Scholar 

  • 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 153:1628–1630

    CAS  PubMed  Google Scholar 

  • 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 45:512–514

    Article  CAS  PubMed  Google Scholar 

  • 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 56:21–27

    CAS  PubMed  Google Scholar 

  • 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 66:2239–2247

    CAS  PubMed  Google Scholar 

  • 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 98:4746–4751

    CAS  PubMed  Google Scholar 

  • 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 56:21–27

    Google Scholar 

  • 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 41:88–96

    Article  PubMed  Google Scholar 

  • 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 169:610–617

    CAS  PubMed  Google Scholar 

  • 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 56:29–36

    CAS  PubMed  Google Scholar 

  • Itil T, Keskiner A, Kiremitci N, Holden JMC (1967) Effect of phencyclidine in chronic schizophrenics. Can Psychiatr Assoc J 12:209–212

    CAS  PubMed  Google Scholar 

  • 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 100:1–9

    CAS  Google Scholar 

  • 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 86:740–744

    CAS  PubMed  Google Scholar 

  • Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308

    CAS  PubMed  Google Scholar 

  • Javitt DC, Zylberman I, Zukin SR, Heresco-Levy U, Lindenmayer JP (1994) Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry 151:1234–1236

    CAS  PubMed  Google Scholar 

  • 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 45:668–679

    CAS  PubMed  Google Scholar 

  • 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 48:627–640

    CAS  PubMed  Google Scholar 

  • 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 23:7586–7591

    CAS  PubMed  Google Scholar 

  • 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 45:608–617

    CAS  PubMed  Google Scholar 

  • 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 51:199–214

    CAS  PubMed  Google Scholar 

  • 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 85:1097–1106

    CAS  PubMed  Google Scholar 

  • Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R (1959) Study of a new schizophrenomimetic drug—sernyl. Arch Neurol Psychiatry 81:363–369

    CAS  Google Scholar 

  • 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 17:141–150

    CAS  PubMed  Google Scholar 

  • 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 114:46–50

    Article  PubMed  Google Scholar 

  • Meltzer HY (1997) Treatment-resistant schizophrenia—the role of clozapine. Curr Med Res Opin 14:1–20

    CAS  PubMed  Google Scholar 

  • 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 97:4926–4931

    Article  CAS  PubMed  Google Scholar 

  • 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 20:106–118

    CAS  PubMed  Google Scholar 

  • Olney JW (2003) Excitotoxicity, apoptosis and neuropsychiatric disorders. Curr Opin Pharmacol 3:101–109

    Article  CAS  PubMed  Google Scholar 

  • 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 156:145–147

    CAS  PubMed  Google Scholar 

  • Schwarcz R, Rassoulpour A, Wu HQ, Medoff D, Tamminga CA, Roberts RC (2001) Increased cortical kynurenate content in schizophrenia. Biol Psychiatry 50:521–530

    Article  CAS  PubMed  Google Scholar 

  • Sheinin A, Shavit S, Benveniste M (2001) Subunit specificity and mechanism of action of NMDA partial agonist d-cycloserine. Neuropharmacology 41:151–158

    Article  CAS  PubMed  Google Scholar 

  • Snyder SH (1981) Dopamine receptors, neuroleptics, and schizophrenia. Am J Psychiatry 138:460–464

    CAS  PubMed  Google Scholar 

  • Stefansson H, Sigurdsson E, Steinhorsdottir V, et al (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892

    Article  PubMed  Google Scholar 

  • 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 52:829–836

    CAS  PubMed  Google Scholar 

  • Tsai G, Yang P, Chung L-C, Lange N, Coyle JT (1998) d-Serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 44:1081–1089

    Article  CAS  PubMed  Google Scholar 

  • 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 156:1822–1825

    CAS  PubMed  Google Scholar 

  • 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)

  • Tsien JZ (2000) Linking Hebb’s coincidence-detection to memory formation. Curr Opin Neurobiol 10:266–273

    Article  CAS  PubMed  Google Scholar 

  • Umbricht D, Koller R, Vollenweider FX, Schmid L (2002) Mismatch negativity predicts psychotic experiences induced by NMDA receptor antagonist in healthy volunteers. Biol Psychiatry 51:400–406

    Article  CAS  PubMed  Google Scholar 

  • 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 40:1298–1300

    Article  PubMed  Google Scholar 

  • 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 16:373–379

    CAS  PubMed  Google Scholar 

  • 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 7:9–24

    CAS  PubMed  Google Scholar 

  • Wroblewska B, Wroblewski JT, Pshenichkin S, Surin A, Sullivan SE, Neale JH (1997) N-Acetylaspartylglutamate selectively activates mGluR3 receptors in transfected cells. J Neurochem 69:174–181

    CAS  PubMed  Google Scholar 

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Acknowledgement

Some of the research discussed in this article was supported by grants from NIH, NARSAD and the Stanley Foundation. Joseph T. Coyle and Guochuan Tsai are inventors of a patent on d-serine for treatment of cognitive impairments that is owned by the Massachusetts General Hospital (US 6228875).

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  1. Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, 02478, USA

    Joseph T. Coyle & Guochuan Tsai

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  1. Joseph T. Coyle
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  2. Guochuan Tsai
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Correspondence to Joseph T. Coyle.

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Coyle, J.T., Tsai, G. The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology 174, 32–38 (2004). https://doi.org/10.1007/s00213-003-1709-2

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