PMID- 31294644 OWN - NLM STAT- MEDLINE DCOM- 20200817 LR - 20200817 IS - 1461-7285 (Electronic) IS - 0269-8811 (Linking) VI - 33 IP - 10 DP - 2019 Oct TI - Therapeutic potential and underlying mechanism of sarcosine (N-methylglycine) in N-methyl-D-aspartate (NMDA) receptor hypofunction models of schizophrenia. PG - 1288-1302 LID - 10.1177/0269881119856558 [doi] AB - BACKGROUND: Compelling animal and clinical studies support the N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia and suggest promising pharmacological agents to ameliorate negative and cognitive symptoms of schizophrenia, including sarcosine, a glycine transporter-1 inhibitor. AIMS AND METHODS: It is imperative to evaluate the therapeutic potential of sarcosine in animal models, which provide indispensable tools for testing drug effects in detail and elucidating the underlying mechanisms. In this study, a series of seven experiments was conducted to investigate the effect of sarcosine in ameliorating behavioral deficits and the underlying mechanism in pharmacological (i.e., MK-801-induced) and genetic (i.e., serine racemase-null mutant (SR(-/-)) mice) NMDAR hypofunction models. RESULTS: In Experiment 1, the acute administration of 500/1000 mg/kg sarcosine (i.p.) had no adverse effects on motor function and serum biochemical responses. In Experiments 2-4, sarcosine significantly alleviated MK-801-induced (0.2 mg/kg) brain abnormalities and behavioral deficits in MK-801-induced and SR(-/-) mouse models. In Experiment 5, the injection of sarcosine enhanced CSF levels of glycine and serine in rat brain. In Experiments 6-7, we show for the first time that sarcosine facilitated NMDAR-mediated hippocampal field excitatory postsynaptic potentials and influenced the movement of surface NMDARs at extrasynaptic sites. CONCLUSIONS: Sarcosine effectively regulated the surface trafficking of NMDARs, NMDAR-evoked electrophysiological activity, brain glycine levels and MK-801-induced abnormalities in the brain, which contributed to the amelioration of behavioral deficits in mouse models of NMDAR hypofunction. FAU - Pei, Ju-Chun AU - Pei JC AD - Department of Psychology, National Taiwan University, Taipei, Taiwan. FAU - Hung, Wei-Li AU - Hung WL AD - Department of Psychology, National Taiwan University, Taipei, Taiwan. FAU - Lin, Bei-Xuan AU - Lin BX AD - Institute of Zoology, National Taiwan University, Taipei, Taiwan. FAU - Shih, Min-Han AU - Shih MH AD - Department of Chemistry, National Taiwan University, Taipei, Taiwan. FAU - Lu, Liang-Yin AU - Lu LY AD - Department of Psychology, National Taiwan University, Taipei, Taiwan. FAU - Luo, Da-Zhong AU - Luo DZ AD - Department of Psychology, National Taiwan University, Taipei, Taiwan. FAU - Tai, Hwan-Ching AU - Tai HC AD - Department of Chemistry, National Taiwan University, Taipei, Taiwan. FAU - Studer, Vincent AU - Studer V AD - Interdisciplinary Institute for Neuroscience, University of Bordeaux, Bordeaux, France. AD - French National Center for Scientific Research (CNRS), Bordeaux, France. FAU - Min, Ming-Yuan AU - Min MY AD - Institute of Zoology, National Taiwan University, Taipei, Taiwan. AD - Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei, Taiwan. AD - Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan. FAU - Lai, Wen-Sung AU - Lai WS AUID- ORCID: 0000-0001-6918-5531 AD - Department of Psychology, National Taiwan University, Taipei, Taiwan. AD - Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei, Taiwan. AD - Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190711 PL - United States TA - J Psychopharmacol JT - Journal of psychopharmacology (Oxford, England) JID - 8907828 RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (Glycine Plasma Membrane Transport Proteins) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 6LR8C1B66Q (Dizocilpine Maleate) RN - EC 5.1.- (Racemases and Epimerases) RN - EC 5.1.1.16 (serine racemase) RN - Z711V88R5F (Sarcosine) SB - IM MH - Animals MH - Behavioral Symptoms/chemically induced/*drug therapy MH - Brain Diseases/chemically induced/*drug therapy MH - Disease Models, Animal MH - Dizocilpine Maleate/pharmacology MH - Excitatory Amino Acid Antagonists/pharmacology MH - Glycine Plasma Membrane Transport Proteins/*agonists MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Racemases and Epimerases/genetics MH - Receptors, N-Methyl-D-Aspartate/*drug effects MH - Sarcosine/administration & dosage/*pharmacology MH - Schizophrenia/*drug therapy/metabolism/pathology/physiopathology OTO - NOTNLM OT - MK-801 OT - NMDAR hypofunction OT - Schizophrenia OT - sarcosine OT - serine racemase (SR) knockout mice EDAT- 2019/07/12 06:00 MHDA- 2020/08/18 06:00 CRDT- 2019/07/12 06:00 PHST- 2019/07/12 06:00 [pubmed] PHST- 2020/08/18 06:00 [medline] PHST- 2019/07/12 06:00 [entrez] AID - 10.1177/0269881119856558 [doi] PST - ppublish SO - J Psychopharmacol. 2019 Oct;33(10):1288-1302. doi: 10.1177/0269881119856558. Epub 2019 Jul 11.