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d-Serine and a glycine transporter-1 inhibitor enhance social memory in rats

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Abstract

Rationale

Glutamatergic abnormalities are involved in the etiology of schizophrenia. Clinical evidence demonstrates that positive modulation of “glycine modulatory sites” on N-methyl-d-aspartic acid (NMDA) receptors improve cognitive deficits as well as positive and negative symptoms in schizophrenic patients.

Objectives

In the present study, we investigated the effects of positive modulation of glycine sites on the NMDA receptor using an agonist of the glycine modulatory site, d-serine, and a glycine transporter-1 inhibitor, (R)-(N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl])sarcosine (NFPS). In particular, we focused on the effects on cognitive functioning using social recognition test in rats. We then compared these effects with those of an atypical antipsychotic clozapine and a typical antipsychotic haloperidol.

Results

Both d-serine and NFPS significantly enhanced social memory in naïve rats, as did clozapine, while the typical antipsychotic haloperidol was ineffective. A noncompetitive NMDA receptor antagonist, MK-801, significantly impaired social memory, which was significantly attenuated by pretreatment with clozapine, but not with haloperidol. Likewise, NFPS significantly improved MK-801-disrupted cognition in the social recognition test. None of these drugs affected social interaction time.

Conclusions

The present results show that stimulation of the glycine modulatory sites on the NMDA receptor either directly with d-serine or by blocking glycine transporter-1 enhances social memory and may be an effective approach for the treatment of the cognitive dysfunction observed in schizophrenic patients.

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References

  • Black MD, Varty GB, Arad M, Barak S, De Levie A, Boulay D, Pichat P, Griebel G, Weiner I (2009) Procognitive and antipsychotic efficacy of glycine transport 1 inhibitors (GlyT1) in acute and neurodevelopmental models of schizophrenia: latent inhibition studies in the rat. Psychopharmacology (Berl) 202:385–396

    Article  CAS  Google Scholar 

  • Boulay D, Pichat P, Dargazanli G, Estenne-Bouhtou G, Terranova JP, Rogacki N, Stemmelin J, Coste A, Lanneau C, Desvignes C, Cohen C, Alonso R, Vigé X, Biton B, Steinberg R, Sevrin M, Oury-Donat F, George P, Bergis O, Griebel G, Avenet P, Scatton B (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 

  • Coyle JT, Tsai G (2004) The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology (Berl) 174:32–38

    Article  CAS  Google Scholar 

  • Danysz W, Parsons CG (1998) Glycine and N-methyl-D-aspartate receptors: physiological significance and possible therapeutic applications. Pharmacol Rev 50:597–664

    CAS  PubMed  Google Scholar 

  • Depoortère R, Dargazanli G, Estenne-Bouhtou G, Coste A, Lanneau C, Desvignes C, Poncelet M, Heaulme M, Santucci V, Decobert M, Cudennec A, Voltz C, Boulay D, Terranova JP, Stemmelin J, Roger P, Marabout B, Sevrin M, Vigé X, Biton B, Steinberg R, Françon D, Alonso R, Avenet P, Oury-Donat F, Perrault G, Griebel G, George P, Soubrié P, Scatton B (2005) Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic. Neuropsychopharmacology 30:1963–1985

    Article  PubMed  CAS  Google Scholar 

  • Di Cara B, Panayi F, Gobert A, Dekeyne A, Sicard D, De Groote L, Millan MJ (2007) Activation of dopamine D1 receptors enhances cholinergic transmission and social cognition: a parallel dialysis and behavioural study in rats. Int J Neuropsychopharmacol 10:383–399

    Article  PubMed  CAS  Google Scholar 

  • Fox GB, Esbenshade TA, Pan JB, Radek RJ, Krueger KM, Yao BB, Browman KE, Buckley MJ, Ballard ME, Komater VA, Miner H, Zhang M, Faghih R, Rueter LE, Bitner RS, Drescher KU, Wetter J, Marsh K, Lemaire M, Porsolt RD, Bennani YL, Sullivan JP, Cowart MD, Decker MW, Hancock AA (2005) Pharmacological properties of ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological characterization and broad preclinical efficacy in cognition and schizophrenia of a potent and selective histamine H3 receptor antagonist. J Pharmacol Exp Ther 313:176–190

    Article  CAS  PubMed  Google Scholar 

  • Fujii DE, Wylie AM, Nathan JH (2004) Neurocognition and long-term prediction of quality of life in outpatients with severe and persistent mental illness. Schizophr Res 69:67–73

    Article  PubMed  Google Scholar 

  • Gao XM, Elmer GI, Adams-Huet B, Tamminga CA (2009) Social memory in mice: disruption with an NMDA antagonist and attenuation with antipsychotic drugs. Pharmacol Biochem Behav 92:236–242

    Article  CAS  PubMed  Google Scholar 

  • Green MF, Kern RS, Braff DL, Mintz J (2000) Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the “right stuff”? Schizophr Bull 26:119–136

    CAS  PubMed  Google Scholar 

  • Harich S, Gross G, Bespalov A (2007) Stimulation of the metabotropic glutamate 2/3 receptor attenuates social novelty discrimination deficits induced by neonatal phencyclidine treatment. Psychopharmacology (Berl) 192:511–519

    Article  CAS  Google Scholar 

  • Hashimoto K, Fujita Y, Ishima T, Chaki S, Iyo M (2008) Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the glycine transporter-1 inhibitor NFPS and D-serine. Eur Neuropsychopharmacol 18:414–421

    Article  CAS  PubMed  Google Scholar 

  • Hlinák Z, Krejcí I (2002) N-Methyl-D-aspartate improved social recognition potency in rats. Neurosci Lett 330:227–230

    Article  PubMed  Google Scholar 

  • Hlinák Z, Krejcí I (2003) Kynurenic acid prevented social recognition deficits induced by MK-801 in rats. Physiol Res 52:805–808

    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 

  • Karasawa J, Hashimoto K, Chaki S (2008) D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats. Behav Brain Res 186:78–83

    Article  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 

  • Kogan JH, Frankland PW, Silva AJ (2000) Long-term memory underlying hippocampus-dependent social recognition in mice. Hippocampus 10:47–56

    Article  CAS  PubMed  Google Scholar 

  • Krystal JH, D’Souza DC, Mathalon D, Perry E, Belger A, Hoffman R (2003) NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berl) 169:215–233

    Article  CAS  Google Scholar 

  • Kuperberg G, Heckers S (2000) Schizophrenia and cognitive function. Curr Opin Neurobiol 10:205–210

    Article  CAS  PubMed  Google Scholar 

  • Lane HY, Chang YC, Liu YC, Chiu CC, Tsai GE (2005) Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. Arch Gen Psychiatry 62:1196–1204

    Article  CAS  PubMed  Google Scholar 

  • Lee KH, Brown WH, Egleston PN, Green RD, Farrow TF, Hunter MD, Parks RW, Wilkinson ID, Spence SA, Woodruff PW (2006) A functional magnetic resonance imaging study of social cognition in schizophrenia during an acute episode and after recovery. Am J Psychiatry 163:1926–1933

    Article  PubMed  Google Scholar 

  • Le Pen G, Kew J, Alberati D, Borroni E, Heitz MP, Moreau JL (2003) Prepulse inhibition deficits of the startle reflex in neonatal ventral hippocampal-lesioned rats: reversal by glycine and a glycine transporter inhibitor. Biol Psychiatry 54:1162–1170

    Article  PubMed  CAS  Google Scholar 

  • Lipina T, Labrie V, Weiner I, Roder J (2005) Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia. Psychopharmacology (Berl) 179:54–67

    Article  CAS  Google Scholar 

  • Loiseau F, Millan MJ (2009) Blockade of dopamine D(3) receptors in frontal cortex, but not in sub-cortical structures, enhances social recognition in rats: similar actions of D(1) receptor agonists, but not of D(2) antagonists. Eur Neuropsychopharmacol 19:23–33

    Article  CAS  PubMed  Google Scholar 

  • Loiseau F, Dekeyne A, Millan MJ (2008) Pro-cognitive effects of 5-HT6 receptor antagonists in the social recognition procedure in rats: implication of the frontal cortex. Psychopharmacology (Berl) 196:93–104

    Article  CAS  Google Scholar 

  • Maaswinkel H, Baars AM, Gispen WH, Spruijt BM (1996) Roles of the basolateral amygdala and hippocampus in social recognition in rats. Physiol Behav 60:55–63

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Meltzer HY, McGurk SR (1999) The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 25:233–255

    CAS  PubMed  Google Scholar 

  • Möhler H, Rudolph U, Boison D, Singer P, Feldon J, Yee BK (2008) Regulation of cognition and symptoms of psychosis: focus on GABA(A) receptors and glycine transporter 1. Pharmacol Biochem Behav 90:58–64

    Article  PubMed  CAS  Google Scholar 

  • Olney JW, Newcomer JW, Farber NB (1999) NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res 33:523–533

    Article  CAS  PubMed  Google Scholar 

  • Sawyer TF, Hengehold AK, Perez WA (1984) Chemosensory and hormonal mediation of social memory in male rats. Behav Neurosci 98:908–913

    Article  CAS  PubMed  Google Scholar 

  • Sekiguchi R, Wolterink G, van Ree JM (1991) Short duration of retroactive facilitation of social recognition in rats. Physiol Behav 50:1253–1256

    Article  CAS  PubMed  Google Scholar 

  • Shimazaki T, Kaku A, Chaki S (2007) Blockade of the metabotropic glutamate 2/3 receptors enhances social memory via the AMPA receptor in rats. Eur J Pharmacol 575:94–97

    Article  CAS  PubMed  Google Scholar 

  • Singer P, Yee BK, Feldon J, Iwasato T, Itohara S, Grampp T, Prenosil G, Benke D, Möhler H, Boison D (2009) Altered mnemonic functions and resistance to N-methyl-d-aspartate receptor antagonism by forebrain conditional knockout of glycine transporter 1. Neuroscience 161:635–654

    Article  CAS  PubMed  Google Scholar 

  • Smith KE, Borden LA, Hartig PR, Branchek T, Weinshank RL (1992) Cloning and expression of a glycine transporter reveal colocalization with NMDA receptors. Neuron 8:927–935

    Article  CAS  PubMed  Google Scholar 

  • Squires AS, Peddle R, Milway SJ, Harley CW (2006) Cytotoxic lesions of the hippocampus do not impair social recognition memory in socially housed rats. Neurobiol Learn Mem 85:95–101

    Article  PubMed  Google Scholar 

  • Thor DH, Holloway WR (1982) Social memory of the male laboratory rat. J Comp Physiol Psychol 96:1000–1006

    Article  Google Scholar 

  • Tsai G, Yang P, Chung LC, 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 G, Lane HY, Yang P, Chong MY, Lange N (2004a) Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 55:452–456

    Article  CAS  PubMed  Google Scholar 

  • Tsai G, Ralph-Williams RJ, Martina M, Bergeron R, Berger-Sweeney J, Dunham KS, Jiang Z, Caine SB, Coyle JT (2004b) Gene knockout of glycine transporter 1: characterization of the behavioral phenotype. Proc Natl Acad Sci USA 101:8485–8490

    Article  CAS  PubMed  Google Scholar 

  • Yee BK, Balic E, Singer P, Schwerdel C, Grampp T, Gabernet L, Knuesel I, Benke D, Feldon J, Mohler H, Boison D (2006) Disruption of glycine transporter 1 restricted to forebrain neurons is associated with a procognitive and antipsychotic phenotypic profile. J Neurosci 26:3169–3181

    Article  CAS  PubMed  Google Scholar 

  • Vanderwolf CH (2001) The hippocampus as an olfacto-motor mechanism: were the classical anatomists right after all? Behav Brain Res 127:25–47

    Article  CAS  PubMed  Google Scholar 

  • Van Kampen M, Selbach K, Schneider R, Schiegel E, Boess F, Schreiber R (2004) AR-R 17779 improves social recognition in rats by activation of nicotinic alpha7 receptors. Psychopharmacology (Berl) 172:375–383

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Discovery Pharmacology, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama, 331-9530, Japan

    Toshiharu Shimazaki, Ayaka Kaku & Shigeyuki Chaki

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  1. Toshiharu Shimazaki
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  2. Ayaka Kaku
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  3. Shigeyuki Chaki
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Correspondence to Shigeyuki Chaki.

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Shimazaki, T., Kaku, A. & Chaki, S. d-Serine and a glycine transporter-1 inhibitor enhance social memory in rats. Psychopharmacology 209, 263–270 (2010). https://doi.org/10.1007/s00213-010-1794-y

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  • DOI: https://doi.org/10.1007/s00213-010-1794-y

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