Skip to main content
SpringerLink
Log in

D-Serine: Basic Aspects with a Focus on Psychosis

  • Reference work entry
  • First Online:
NeuroPsychopharmacotherapy

  • 81 Accesses

Abstract

Based on the glutamate hypothesis of schizophrenia postulating hypofunction of the N-methyl-D-aspartate type glutamate receptor (NMDA receptor) consisting of GluN1 and GluN2 subunits, D-serine has been selected as a candidate agent that is expected to satisfy an unmet need to ameliorate antipsychotic-resistant negative and cognitive symptoms in schizophrenia by recovering the NMDA receptor disturbance as one of its coagonists. Meta-analyses of randomized controlled trials of D-serine given with currently available antipsychotic drugs in patients with schizophrenia have consistently shown a significant reduction in the rating scores of their negative symptoms although D-serine has not yet been approved for clinical use. This chapter begins with verification of the evidence for the involvement of diminished NMDA receptor-mediated transmission in the pathophysiology of schizophrenia, accumulated data illustrating the plausible mechanisms from the hypofunction to the positive, negative, and cognitive symptoms and the relationships between the NMDA dysfunction and the well-established dopamine hypothesis assuming cerebral hyperdopaminergic activities. The consecutive parts verify the rationales for application of D-serine and other agonists acting at the glycine site of the NMDA receptor for development of NMDA receptor activity-enhancing therapy of schizophrenia and outline the preclinical and clinical studies using these agonists. The NMDA receptor targeting strategy is challenged by the results that the add-on treatments with augmentation of the extracellular glycine concentrations have failed to improve the antipsychotic-refractory symptoms of schizophrenia patients. To address this issue, the latter parts raise the possibility to restore functioning of the forebrain NMDA receptor by upregulating endogenous D-serine signaling at the synapses by modifying the molecules that compose the metabolic pathways and regulatory systems of the extracellular levels of D-serine.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 949.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 1,399.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aalto S, Ihalainen J, Hirvonen J, Kajander J, Scheinin H, Tanila H, et al. Cortical glutamate-dopamine interaction and ketamine-induced psychotic symptoms in man. Psychopharmacology (Berl). 2005;182:375–83.

    CAS  PubMed  Google Scholar 

  • American Psychiatric Association. Schizophrenia spectrum and other psychotic disorders. In: American Psychiatric Association, editor. Diagnostic and statistical manual of mental disorders (DSM-5®). 5th ed. Washington, DC: Amer Psychiatric Pub Inc; 2013. p. 87–122.

    Google Scholar 

  • Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol. 1983;79:565–575.

    Google Scholar 

  • Balu DT, Takagi S, Puhl MD, Benneyworth MA, Coyle JT. D-serine and serine racemase are localized to neurons in the adult mouse and human forebrain. Cell Mol Neurobiol. 2014;34:419–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Basu AC, Tsai GE, Ma CL, Ehmsen JT, Mustafa AK, Han L, et al. Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior. Mol Psychiatry. 2009;14:719–27.

    CAS  PubMed  Google Scholar 

  • Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci. 2010;13:76–83.

    CAS  PubMed  Google Scholar 

  • Bendikov I, Nadri C, Amar S, Panizzutti R, De Miranda J, Wolosker H, et al. A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia. Schizophr Res. 2007;90:41–51.

    PubMed  Google Scholar 

  • Benneyworth MA, Li Y, Basu AC, Bolshakov VY, Coyle JT. Cell selective conditional null mutations of serine racemase demonstrate a predominate localization in cortical glutamatergic neurons. Cell Mol Neurobiol. 2012;32:613–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bodner O, Radzishevsky I, Foltyn VN, Touitou A, Valenta AC, Rangel IF, et al. D-serine signaling and NMDAR-mediated synaptic plasticity are regulated by system A-type of glutamine/D-serine dual transporters. J Neurosci. 2020;40:6489–502.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bouwmans C, de Sonneville C, Mulder CL, Hakkaart-Van RL. Employment and the associated impact on quality of life in people diagnosed with schizophrenia. Neuropsychiatr Dis Treat. 2015;11:2125–42.

    PubMed  PubMed Central  Google Scholar 

  • Brouwer A, Luykx JJ, van Boxmeer L, Bakker SC, Kahn RS. NMDA-receptor coagonists in serum, plasma, and cerebrospinal fluid of schizophrenia patients: a meta-analysis of case-control studies. Neurosci Biobehav Rev. 2013 Sep;37(8):1587–96. https://doi.org/10.1016/j.neubiorev.2013.

    Article  CAS  PubMed  Google Scholar 

  • Bugarski-Kirola D, Blaettler T, Arango C, Fleischhacker WW, Garibaldi G, Wang A, et al. Bitopertin in negative symptoms of schizophrenia-results from the phase III FlashLyte and DayLyte studies. Biol Psychiatry. 2017;82:8–16.

    CAS  PubMed  Google Scholar 

  • Castillo-Gómez E, Oliveira B, Tapken D, Bertrand S, Klein-Schmidt C, Pan H et al. All naturally occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential irrespective of epitope and immunoglobulin class. Mol Psychiatry. 2017;22:1776–1784.

    Google Scholar 

  • Chang CH, Lin CH, Liu CY, Chen SJ, Lane HY. Efficacy and cognitive effect of sarcosine (N-methylglycine) in patients with schizophrenia: a systematic review and meta-analysis of double-blind randomised controlled trials. J Psychopharmacol. 2020;34:495–505.

    PubMed  Google Scholar 

  • Chen CH, Cheng MC, Liu CM, Liu CC, Lin KH, Hwu HG. Seroprevalence survey of selective anti-neuronal autoantibodies in patients with first-episode schizophrenia and chronic schizophrenia. Schizophr Res. 2017;190:28–31.

    PubMed  Google Scholar 

  • Cho SE, Na KS, Cho SJ, Kang SG. Low d-serine levels in schizophrenia: a systematic review and meta-analysis. Neurosci Lett. 2016;634:42–51.

    CAS  PubMed  Google Scholar 

  • Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci U S A. 2002;99:13675–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Connel PH. Amphetamine Psychosis. Maudsley monographs number five. London: Chapman & Hall Ltd; 1958. p. 123.

    Google Scholar 

  • Contreras PC. D-serine antagonized phencyclidine- and MK-801-induced stereotyped behavior and ataxia. Neuropharmacology. 1990;29:291–3.

    CAS  PubMed  Google Scholar 

  • Curcio L, Podda MV, Leone L, Piacentini R, Mastrodonato A, Cappelletti P, et al. Reduced D-serine levels in the nucleus accumbens of cocaine-treated rats hinder the induction of NMDA receptor-dependent synaptic plasticity. Brain. 2013;136:1216–30.

    PubMed  Google Scholar 

  • Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61:25–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, Leypoldt F, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol. 2019;18:1045–57.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Deutch AY, Tam SY, Freeman AS, Bowers MB Jr, Roth RH. Mesolimbic and mesocortical dopamine activation induced by phencyclidine: contrasting pattern to striatal response. Eur J Pharmacol. 1987;134:257–64.

    CAS  PubMed  Google Scholar 

  • Dumin E, Bendikov I, Foltyn VN, Misumi Y, Ikehara Y, Kartvelishvily E, et al. Modulation of D-serine levels via ubiquitin-dependent proteasomal degradation of serine racemase. J Biol Chem. 2006;281(29):20291–302.

    CAS  PubMed  Google Scholar 

  • Dunlop DS, Neidle A. The origin and turnover of D-serine in brain. Biochem Biophys Res Commun. 1997;235:26–30.

    CAS  PubMed  Google Scholar 

  • Featherstone RE, Melnychenko O, Siegel SJ. Mismatch negativity in preclinical models of schizophrenia. Schizophr Res. 2018;191:35–42.

    PubMed  Google Scholar 

  • Fone KCF, Watson DJG, Billiras RI, Sicard DI, Dekeyne A, Rivet JM, et al. Comparative pro-cognitive and neurochemical profiles of glycine modulatory site agonists and glycine reuptake inhibitors in the rat: potential relevance to cognitive dysfunction and its management. Mol Neurobiol. 2020;57:2144–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Goff DC, Henderson DC, Evins AE, Amico E. A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia. Biol Psychiatry. 1999;45:512–4.

    CAS  PubMed  Google Scholar 

  • Goh KK, Wu TH, Chen CH, Lu ML. Efficacy of N-methyl-D-aspartate receptor modulator augmentation in schizophrenia: a meta-analysis of randomised, placebo-controlled trials. J Psychopharmacol. 2021;35:236–52.

    CAS  PubMed  Google Scholar 

  • Hashimoto A, Nishikawa T, Oka T, Takahashi K. D-alanine inhibits methamphetamine-induced hyperactivity in rats. Eur J Pharmacol. 1991;202:105–7.

    CAS  PubMed  Google Scholar 

  • Hashimoto A, Nishikawa T, Hayashi T, Fujii N, Harada K, Oka T, et al. The presence of free D-serine in rat brain. FEBS Lett. 1992a;296:33–6.

    CAS  PubMed  Google Scholar 

  • Hashimoto A, Nishikawa T, Oka T, Takahashi K, Hayashi T. Determination of free amino acid enantiomers in rat brain and serum by high-performance liquid chromatography after derivatization with N-tert.-butyloxycarbonyl-L-cysteine and o-phthaldialdehyde. J Chromatogr. 1992b;582:41–8.

    CAS  PubMed  Google Scholar 

  • Hashimoto A, Nishikawa T, Konno R, Niwa A, Yasumura Y, Oka T, et al. Free D-serine, D-aspartate and D-alanine in central nervous system and serum in mutant mice lacking D-amino acid oxidase. Neurosci Lett. 1993a;152:33–6.

    CAS  PubMed  Google Scholar 

  • Hashimoto A, Nishikawa T, Oka T, Takahashi K. Endogenous D-serine in rat brain: N-methyl-D-aspartate receptor-related distribution and aging. J Neurochem. 1993b;60:783–6.

    CAS  PubMed  Google Scholar 

  • Hashimoto A, Oka T, Nishikawa T. Extracellular concentration of endogenous free D-serine in the rat brain as revealed by in vivo microdialysis. Neuroscience. 1995;66:635–43.

    CAS  PubMed  Google Scholar 

  • Hata N, Nishikawa T, Umino A, Takahashi K. Evidence for involvement of N-methyl-D-aspartate receptor in tonic inhibitory control of dopaminergic transmission in rat medial frontal cortex. Neurosci Lett. 1990;120:101–4.

    CAS  PubMed  Google Scholar 

  • Hayashi F, Takahashi K, Nishikawa T. Uptake of D- and L-serine in C6 glioma cells. Neurosci Lett. 1997;239:85–88.

    Google Scholar 

  • Henneberger C, Papouin T, Oliet SH, Rusakov DA. Long-term potentiation depends on release of D-serine from astrocytes. Nature. 2010;463:232–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hiraoka S, Kajii Y, Kuroda Y, Umino A, Nishikawa T. The development- and phencyclidine-regulated induction of synapse-associated protein-97 gene in the rat neocortex. Eur Neuropsychopharmacol. 2010;20:176–86.

    CAS  PubMed  Google Scholar 

  • Horio M, Kohno M, Fujita Y, Ishima T, Inoue R, Mori H, et al. Levels of D-serine in the brain and peripheral organs of serine racemase (Srr) knock-out mice. Neurochem Int. 2011;59:853–9.

    CAS  PubMed  Google Scholar 

  • Hu W, MacDonald ML, Elswick DE, Sweet RA. The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann N Y Acad Sci. 2015;1338:38–57.

    CAS  PubMed  Google Scholar 

  • Ibrahim HM, Hogg AJ Jr, Healy DJ, Haroutunian V, Davis KL, Meador-Woodruff JH. Ionotropic glutamate receptor binding and subunit mRNA expression in thalamic nuclei in schizophrenia. Am J Psychiatry. 2000;157:1811–23.

    CAS  PubMed  Google Scholar 

  • Ishimaru M, Kurumaji A, Toru M. Increases in strychnine-insensitive glycine binding sites in cerebral cortex of chronic schizophrenics: evidence for glutamate hypothesis. Biol Psychiatry. 1994;35:84–95.

    CAS  PubMed  Google Scholar 

  • Ishiwata S, Ogata S, Umino A, Shiraku H, Ohashi Y, Kajii Y, et al. Increasing effects of S-methyl-L-cysteine on the extracellular D-serine concentrations in the rat medial frontal cortex. Amino Acids. 2013a;44:1391–5.

    CAS  PubMed  Google Scholar 

  • Ishiwata S, Umino A, Umino M, Yorita K, Fukui K, Nishikawa T. Modulation of extracellular d-serine content by calcium permeable AMPA receptors in rat medial prefrontal cortex as revealed by in vivo microdialysis. Int J Neuropsychopharmacol. 2013b;16:1395–406.

    CAS  PubMed  Google Scholar 

  • Ishiwata S, Umino A, Balu DT, Coyle JT, Nishikawa T. Neuronal serine racemase regulates extracellular D-serine levels in the adult mouse hippocampus. J Neural Transm (Vienna). 2015;122:1099–103.

    CAS  PubMed  Google Scholar 

  • Ishiwata S, Hattori K, Sasayama D, Teraishi T, Miyakawa T, Yokota Y, et al. Plasma and cerebrospinal fluid G72 protein levels in schizophrenia and major depressive disorder. Psychiatry Res. 2017;254:244–50.

    CAS  PubMed  Google Scholar 

  • Ishiwata S, Umino A, Nishikawa T. Involvement of neuronal and glial activities in control of the extracellular d-serine concentrations by the AMPA glutamate receptor in the mouse medial prefrontal cortex. Neurochem Int. 2018;119:120–5.

    CAS  PubMed  Google Scholar 

  • Iwama H, Takahashi K, Kure S, Hayashi F, Narisawa K, Tada K, et al. Depletion of cerebral D-serine in non-ketotic hyperglycinemia: possible involvement of glycine cleavage system in control of endogenous D-serine. Biochem Biophys Res Commun. 1997;231:793–6.

    CAS  PubMed  Google Scholar 

  • Iwata Y, Nakajima S, Plitman E, Mihashi Y, Caravaggio F, Chung JK, et al. Neurometabolite levels in antipsychotic-naïve/free patients with schizophrenia: A systematic review and meta-analysis of 1H-MRS studies. Prog Neuropsychopharmacol Biol Psychiatry. 2018;86:340–52.

    CAS  PubMed  Google Scholar 

  • Javitt DC, Balla A, Burch S, Suckow R, Xie S, Sershen H. Reversal of phencyclidine-induced dopaminergic dysregulation by N-methyl-D-aspartate receptor/glycine-site agonists. Neuropsychopharmacology. 2004;29:300–7.

    CAS  PubMed  Google Scholar 

  • Johnson KM, Jones SM. Neuropharmacology of phencyclidine: basic mechanisms and therapeutic potential. Annu Rev Pharmacol Toxicol. 1990;30:707–50.

    CAS  PubMed  Google Scholar 

  • Kakegawa W, Miyoshi Y, Hamase K, Matsuda S, Matsuda K, Kohda K, et al. D-serine regulates cerebellar LTD and motor coordination through the δ2 glutamate receptor. Nat Neurosci. 2011;14:603–11.

    CAS  PubMed  Google Scholar 

  • Kanematsu S, Ishii S, Umino A, Fujihira T, Kashiwa A, Yamamoto N, et al. Evidence for involvement of glial cell activity in the control of extracellular D-serine contents in the rat brain. J Neural Transm (Vienna). 2006;113:1717–21.

    CAS  PubMed  Google Scholar 

  • Kantrowitz JT, Epstein ML, Beggel O, Rohrig S, Lehrfeld JM, Revheim N, et al. Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist D-serine. Brain. 2016;139(Pt 12):3281–95.

    PubMed  PubMed Central  Google Scholar 

  • Kantrowitz JT, Nolan KA, Epstein ML, Lehrfeld N, Shope C, Petkova E, et al. Neurophysiological effects of bitopertin in schizophrenia. J Clin Psychopharmacol. 2017;37:447–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kantrowitz JT, Epstein ML, Lee M, Lehrfeld N, Nolan KA, Shope C, et al. Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: correlation with symptoms. Schizophr Res. 2018;191:70–9.

    PubMed  Google Scholar 

  • Kartvelishvily E, Shleper M, Balan L, Dumin E, Wolosker H. Neuron-derived D-serine release provides a novel means to activate N-methyl-D-aspartate receptors. J Biol Chem. 2006;281:14151–14162.

    Google Scholar 

  • Kashiwa A, Nishikawa T, Nishijima K, Umino A, Takahashi K. Dizocilpine (MK-801) elicits a tetrodotoxin-sensitive increase in extracellular release of dopamine in rat medial frontal cortex. Neurochem Int. 1995;26:269–79.

    CAS  PubMed  Google Scholar 

  • Kayser MS, Dalmau J. Anti-NMDA receptor encephalitis in psychiatry. Curr Psychiatry Rev. 2011;7:189–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Keller S, Punzo D, Cuomo M, Affinito O, Coretti L, Sacchi S, et al. DNA methylation landscape of the genes regulating D-serine and D-aspartate metabolism in post-mortem brain from controls and subjects with schizophrenia. Sci Rep. 2018;8:10163.

    PubMed  PubMed Central  Google Scholar 

  • Kidd LR, Lyons SC, Lloyd G. Paediatric procedural sedation using ketamine in a UK emergency department: a 7 year review of practice. Br J Anaesth. 2016;116:518–23.

    CAS  PubMed  Google Scholar 

  • Konno R, Yasumura Y. Brain and kidney D-amino acid oxidases are coded by a single gene in the mouse. J Neurochem. 1984;42:584–6.

    CAS  PubMed  Google Scholar 

  • Krebs HA. Metabolism of amino-acids: The synthesis of glutamine from glutamic acid and ammonia, and the enzymic hydrolysis of glutamine in animal tissues. Biochem J. 1935;29:1951–69.

    Google Scholar 

  • Kumashiro S, Hashimoto A, Nishikawa T. Free D-serine in post-mortem brains and spinal cords of individuals with and without neuropsychiatric diseases. Brain Res. 1995;681:117–25.

    CAS  PubMed  Google Scholar 

  • Kuppili PP, Menon V, Sathyanarayanan G, Sarkar S, Andrade C. Efficacy of adjunctive D-Cycloserine for the treatment of schizophrenia: a systematic review and meta-analysis of randomized controlled trials. J Neural Transm (Vienna). 2021;128:253–62.

    CAS  PubMed  Google Scholar 

  • Labrie V, Fukumura R, Rastogi A, Fick LJ, Wang W, Boutros PC, et al. Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model. Hum Mol Genet. 2009;18:3227–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lahti AC, Holcomb HH, Gao X-M, Tamminga CA. NMDA-sensitive glutamate antagonism: a human model for psychosis. Neuropsychopharmacol. 1999;21:S158–69.

    CAS  Google Scholar 

  • Lane HY, Huang CL, Wu PL, Liu YC, Chang YC, Lin PY, et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry. 2006;60:645–9.

    CAS  PubMed  Google Scholar 

  • Lane HY, Lin CH, Green MF, Hellemann G, Huang CC, Chen PW, et al. Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor. JAMA Psychiatry. 2013;70:1267–75.

    CAS  PubMed  Google Scholar 

  • Laruelle M. Imaging dopamine transmission in schizophrenia. A review and meta-analysis. Q J Nucl Med. 1998;42:211–21.

    CAS  PubMed  Google Scholar 

  • Le Bail M, Martineau M, Sacchi S, Yatsenko N, Radzishevsky I, Conrod S, et al. Identity of the NMDA receptor coagonist is synapse specific and developmentally regulated in the hippocampus. Proc Natl Acad Sci U S A. 2015;112:E204–13.

    PubMed  Google Scholar 

  • Lin CH, Lin CH, Chang YC, Huang YJ, Chen PW, Yang HT, et al. Sodium benzoate, a D-amino acid oxidase inhibitor, added to clozapine for the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Biol Psychiatry. 2018;84:422–32.

    Google Scholar 

  • Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R. Study of a new schizophrenomimetic drug; sernyl. AMA Arch Neurol Psychiatry. 1959;81:363–9.

    CAS  PubMed  Google Scholar 

  • Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, et al. Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology. 1997;17:141–50.

    CAS  PubMed  Google Scholar 

  • Martineau M, Shi T, Puyal J, Knolhoff AM, Dulong J, Gasnier B, et al. Storage and uptake of D-serine into astrocytic synaptic-like vesicles specify gliotransmission. J Neurosci. 2013;33:3413–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Matsui T, Sekiguchi M, Hashimoto A, Tomita U, Nishikawa T, Wada K. Functional comparison of D-serine and glycine in rodents: the effect on cloned NMDA receptors and the extracellular concentration. J Neurochem. 1995;65:454–8.

    CAS  PubMed  Google Scholar 

  • Matsuura A, Fujita Y, Iyo M, Hashimoto K. Effects of sodium benzoate on pre-pulse inhibition deficits and hyperlocomotion in mice after administration of phencyclidine. Acta Neuropsychiatr. 2015;27:159–67.

    PubMed  Google Scholar 

  • McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia – an overview. JAMA Psychiatry. 2020;77:201–10.

    PubMed  Google Scholar 

  • Miya K, Inoue R, Takata Y, Abe M, Natsume R, Sakimura K, et al. Serine racemase is predominantly localized in neurons in mouse brain. J Comp Neurol. 2008;510:641–54.

    CAS  PubMed  Google Scholar 

  • Miyoshi Y, Konno R, Sasabe J, Ueno K, Tojo Y, Mita M, et al. Alteration of intrinsic amounts of D-serine in the mice lacking serine racemase and D-amino acid oxidase. Amino Acids. 2012;43:1919–31.

    CAS  PubMed  Google Scholar 

  • Moghaddam B, Adams BW. Reversal of phencyclidine effects by a Group II metabotropic glutamate receptor agonist in rats. Science. 1998;281:1349–52.

    CAS  PubMed  Google Scholar 

  • Mothet JP, Parent AT, Wolosker H, Brady RO Jr, Linden DJ, Ferris CD et al. D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. 2000;97:4926–4931.

    Google Scholar 

  • Naur P, Hansen KB, Kristensen AS, Dravid SM, Pickering DS, Olsen L, et al. Ionotropic glutamate-like receptor delta2 binds D-serine and glycine. Proc Natl Acad Sci U S A. 2007;104:14116–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Neame S, Safory H, Radzishevsky I, Touitou A, Marchesani F, Marchetti M, et al. The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle. Proc Natl Acad Sci U S A. 2019;116:20736–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nishijima K, Kashiwa A, Nishikawa T. Preferential stimulation of extracellular release of dopamine in rat frontal cortex to striatum following competitive inhibition of the N-methyl-D-aspartate receptor. J Neurochem. 1994;63:375–8.

    CAS  PubMed  Google Scholar 

  • Nishijima K, Kashiwa A, Hashimoto A, Iwama H, Umino A, Nishikawa T. Differential effects of phencyclidine and methamphetamine on dopamine metabolism in rat frontal cortex and striatum as revealed by in vivo dialysis. Synapse. 1996;22:304–12.

    CAS  PubMed  Google Scholar 

  • Nishikawa T. Analysis of free D-serine in mammals and its biological relevance. J Chromatogr B Analyt Technol Biomed Life Sci. 2011;879:3169–83.

    CAS  PubMed  Google Scholar 

  • Nishikawa T, Hashimoto A, Tanii Y, Umino A, Kashiwa A, Kumashiro S, et al. Disturbed neurotransmission via the N-methyl-D-aspartate receptor and schizophrenia. In: Moroji T, Yamamoto K, editors. The biology of schizophrenia. Development of psychiatry series. Amsterdam: Elsevier; 1994. p. 197–207.

    Google Scholar 

  • Papouin T, Ladépêche L, Ruel J, Sacchi S, Labasque M, Hanini M, et al. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell. 2012;150:633–46.

    CAS  PubMed  Google Scholar 

  • Perez EJ, Tapanes SA, Loris ZB, Balu DT, Sick TJ, Coyle JT, et al. Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury. J Clin Invest. 2017;127:3114–25.

    PubMed  PubMed Central  Google Scholar 

  • Pérez-Otaño I, Larsen RS, Wesseling JF. Emerging roles of GluN3-containing NMDA receptors in the CNS. Nat Rev Neurosci. 2016;17:623–35.

    PubMed  Google Scholar 

  • Petersen RC, Stillman RC, editors. Phencyclidine (PCP) abuse: an appraisal. National Institute on Drug Abuse Research Monographs, superintendent of documents. Washington, DC: U. S. Government Printing Office; 1978. p. 313.

    Google Scholar 

  • Pilowsky LS, Bressan RA, Stone JM, Erlandsson K, Mulligan RS, Krystal JH, et al. First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychiatry. 2006;11:118–9.

    CAS  PubMed  Google Scholar 

  • Plitman E, Iwata Y, Caravaggio F, Nakajima S, Chung JK, Gerretsen P, et al. Kynurenic acid in schizophrenia: a systematic review and meta-analysis. Schizophr Bull. 2017;43:764–77.

    PubMed  PubMed Central  Google Scholar 

  • Potkin SG, Jin Y, Bunney BG, Costa J, Gulasekaram B. Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia. Am J Psychiatry. 1999;156:145–7.

    CAS  PubMed  Google Scholar 

  • Rao TS, Kim HS, Lehmann J, Martin LL, Wood PL. Interactions of phencyclidine receptor agonist MK-801 with dopaminergic system: regional studies in the rat. J Neurochem. 1990;54:1157–62.

    CAS  PubMed  Google Scholar 

  • Reich DL, Silvay G. Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth. 1989;36:186–97.

    CAS  PubMed  Google Scholar 

  • Rosenberg H, Ennor AH. Occurrence of free D-serine in the earthworm. Nature. 1960;187:617–8.

    CAS  PubMed  Google Scholar 

  • Sato D, Umino A, Kaneda K, Takigawa M, Nishikawa T. Developmental changes in distribution patterns of phencyclidine-induced c-Fos in rat forebrain. Neurosci Lett. 1997;239:21–4.

    CAS  PubMed  Google Scholar 

  • Scheer S, John RM. Anti-N-methyl-D-aspartate receptor encephalitis in children and adolescents. J Pediatr Health Care. 2016;30:347–58.

    PubMed  Google Scholar 

  • Schell MJ, Molliver ME, Snyder SH. D-Serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci U S A. 1995;92:3948–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.

    PubMed Central  Google Scholar 

  • Schwartz RH, Einhorn A. PCP intoxication in seven young children. Pediatr Emerg Care. 1986;2:238–41.

    CAS  PubMed  Google Scholar 

  • Sershen H, Hashim A, Dunlop DS, Suckow RF, Cooper TB, Javitt DC. Modulating NMDA receptor function with D-amino acid oxidase inhibitors: understanding functional activity in PCP-treated mouse model. Neurochem Res. 2016;41:398–408.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shimazu D, Yamamoto N, Umino A, Ishii S, Sakurai S, Nishikawa T. Inhibition of D-serine accumulation in the Xenopus oocyte by expression of the rat ortholog of human 3′-phosphoadenosine 5′-phosphosulfate transporter gene isolated from the neocortex as D-serine modulator-1. J Neurochem. 2006;96:30–42.

    CAS  PubMed  Google Scholar 

  • Singh SP, Singh V. Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia. CNS Drugs. 2011;25:859–85.

    CAS  PubMed  Google Scholar 

  • Srinivasan NG, Corrigan JJ, Meister A. D-Serine in the blood of the silkworm Bombyx mori and other lepidoptera. J Biol Chem. 1962;237:3844–5.

    CAS  PubMed  Google Scholar 

  • Steffek AE, Haroutunian V, Meador-Woodruff JH. Serine racemase protein expression in cortex and hippocampus in schizophrenia. Neuroreport. 2006;17:1181–5.

    CAS  PubMed  Google Scholar 

  • Steiner J, Walter M, Glanz W, Sarnyai Z, Bernstein HG, Vielhaber S, et al. Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatry. 2013;70:271–8.

    PubMed  Google Scholar 

  • Takahashi K, Hayashi F, Nishikawa T. In vivo evidence for the link between L- and D-serine metabolism in rat cerebral cortex. J Neurochem. 1997;69:1286–90.

    CAS  PubMed  Google Scholar 

  • Tanii Y, Nishikawa T, Hashimoto A, Takahashi K. Stereoselective inhibition by D- and L-alanine of phencyclidine-induced locomotor stimulation in the rat. Brain Res. 1991;563:281–4.

    CAS  PubMed  Google Scholar 

  • Tanii Y, Nishikawa T, Hashimoto A, Takahashi K. Stereoselective antagonism by enantiomers of alanine and serine of phencyclidine-induced hyperactivity, stereotypy and ataxia in the rat. J Pharmacol Exp Ther. 1994;269:1040–8.

    CAS  PubMed  Google Scholar 

  • Tanii Y, Nishikawa T, Hibino H, Takahashi K. Effects of allosteric agonists for N-methyl-D-aspartate receptor and their derivatives on phencyclidine-induced abnormal behavior in the rat. Brain Sci Mental Disord (Present: Jpn J Biol Psychiatry), 1991b; 2:497–502 (in Japanese with English abstract). Erratum in: Jpn J Biol Psychiatry. 2010;21:126.

    Google Scholar 

  • Tsai GE, Lin PY. Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis. Curr Pharm Des. 2010;16:522–37.

    CAS  PubMed  Google Scholar 

  • Tsai GE, Yang P, Chung LC, Tsai IC, Tsai CW, Coyle JT. D-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry. 1999;156:1822–5.

    CAS  PubMed  Google Scholar 

  • Umino A, Takahashi K, Nishikawa T. Characterization of the phencyclidine-induced increase in prefrontal cortical dopamine metabolism in the rat. Br J Pharmacol. 1998;124:377–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Umino A, Ishiwata S, Iwama H, Nishikawa T. Evidence for tonic control by the GABAA receptor of extracellular D-Serine concentrations in the medial prefrontal cortex of rodents. Front Mol Neurosci. 2017;10:240.

    PubMed  PubMed Central  Google Scholar 

  • Umino M, Umino A, Nishikawa T. Effects of selective calcium-permeable AMPA receptor blockade by IEM 1460 on psychotomimetic-induced hyperactivity in the mouse. J Neural Transm (Vienna). 2018;125:705–11.

    CAS  PubMed  Google Scholar 

  • Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J. Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacol. 1997;7:25–38.

    CAS  PubMed  Google Scholar 

  • Weimar WR, Neims AH. The development of D-amino acid oxidase in rat cerebellum. J Neurochem. 1977;29:649–56.

    CAS  PubMed  Google Scholar 

  • Welch MJ, Correa GA. PCP intoxication in young children and infants. Clin Pediatr (Phila). 1980;19:510–4.

    CAS  PubMed  Google Scholar 

  • White PF, Way WL, Trevor AJ. Ketamine – its pharmacology and therapeutic uses. Anesthesiology. 1982;56:119–36.

    CAS  PubMed  Google Scholar 

  • Wolosker H, Blackshaw S, Snyder SH. Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc Natl Acad Sci U S A. 1999a;96:13409–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wolosker H, Sheth KN, Takahashi M, Mothet JP, Brady RO Jr, Ferris CD, et al. Purification of serine racemase: biosynthesis of the neuromodulator D-serine. Proc Natl Acad Sci U S A. 1999b;96:721–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wong JM, Folorunso OO, Barragan EV, Berciu C, Harvey TL, Coyle JT, et al. Postsynaptic serine racemase regulates NMDA receptor function. J Neurosci. 2020;40:9564–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yagi K, Nagatsu T, Ozawa T. Inhibitory action of chlorpromazine on the oxidation of d-amino-acid in the diencephalon part of the brain. Nature. 1956;177:891–2.

    Google Scholar 

  • Yamamoto N, Tomita U, Umino A, Nishikawa T. Uptake of D-serine by synaptosomal P2 fraction isolated from rat brain. Synapse. 2001;42:84–6.

    CAS  PubMed  Google Scholar 

  • Yang Y, Ge W, Chen Y, Zhang Z, Shen W, Wu C, et al. Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. Proc Natl Acad Sci U S A. 2003;100:15194–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang JH, Wada A, Yoshida K, Miyoshi Y, Sayano T, Esaki K, et al. Brain-specific Phgdh deletion reveals a pivotal role for L-serine biosynthesis in controlling the level of D-serine, an N-methyl-D-aspartate receptor co-agonist, in adult brain. J Biol Chem. 2010;285:41380–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yonezawa Y, Kuroki T, Kawahara T, Tashiro N, Uchimura H. Involvement of gamma-aminobutyric acid neurotransmission in phencyclidine-induced dopamine release in the medial prefrontal cortex. Eur J Pharmacol. 1998;341:45–56.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, and Pharmacological Research Center, Showa University, Tokyo, Japan

    Toru Nishikawa, Asami Umino & Masakazu Umino

Authors
  1. Toru Nishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Asami Umino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masakazu Umino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toru Nishikawa .

Editor information

Editors and Affiliations

  1. Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy, University Hospital Wuerzburg, Wuerzburg, Germany

    Peter Riederer

  2. Institute of Psychological Medicine (IPM), Soyen, Germany

    Gerd Laux

  3. Centre for Research Promotion and Support, Fujita Health University, Toyoake, Aichi, Japan

    Toshiharu Nagatsu

  4. Center Translational Res Neurol Diseases, Dalian Med Uni Shanghai Inst Health Sc Center Translational Res Neurol Diseases, Dalian, China

    Weidong Le

  5. Würzburg, Germany

    Christian Riederer

Section Editor information

  1. Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy, University Hospital Wuerzburg, Wuerzburg, Germany

    Peter Riederer

  2. Department of Psychiatry, University of Southern Denmark, Odense, Denmark

    Peter Riederer

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Nishikawa, T., Umino, A., Umino, M. (2022). D-Serine: Basic Aspects with a Focus on Psychosis. In: Riederer, P., Laux, G., Nagatsu, T., Le, W., Riederer, C. (eds) NeuroPsychopharmacotherapy. Springer, Cham. https://doi.org/10.1007/978-3-030-62059-2_470

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-62059-2_470

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-62058-5

  • Online ISBN: 978-3-030-62059-2

  • eBook Packages: MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation