Hashimoto Kenji, Fujita Yuko, Ishima Tamaki, Chaki Shigeyuki, Iyo Masaomi
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba, Japan.
Eur Neuropsychopharmacol. 2008 Jun;18(6):414-21. doi: 10.1016/j.euroneuro.2007.07.009. Epub 2007 Sep 4.
Accumulating evidence suggests that the glycine modulatory site on the NMDA receptor could be potential therapeutic target for cognitive deficits in schizophrenia. The present study was undertaken to examine the effects of the glycine transporter-1 (GlyT-1) inhibitor, (R)-(N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine (NFPS), on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of NFPS (1.0 and 3.0 mg/kg/day) or D-serine (600 mg/kg/day). However, PCP-induced cognitive deficits were not improved by a single administration of NFPS (3.0 mg/kg). Furthermore, Western blot analysis revealed that levels of GlyT-1 in the hippocampus, but not frontal cortex, of the PCP (10 mg/kg/day for 10 days)-treated mice were significantly higher than those of saline-treated mice. An in vivo microdialysis study revealed that repeated PCP administration significantly decreased the extracellular levels of glycine in the hippocampus, but not frontal cortex, of mice. These findings suggest that repeated PCP administration increased the density of GlyT-1 in the hippocampus of mouse brain, and that the GlyT-1 inhibitor NFPS could ameliorate cognitive deficits in mice after repeated administration of PCP.
越来越多的证据表明，N-甲基-D-天冬氨酸（NMDA）受体上的甘氨酸调节位点可能是治疗精神分裂症认知缺陷的潜在靶点。本研究旨在探讨甘氨酸转运体-1（GlyT-1）抑制剂（R）-（N-[3-（4'-氟苯基）-3-（4'-苯基苯氧基）丙基]）肌氨酸（NFPS）对反复给予NMDA受体拮抗剂苯环利定（PCP）后小鼠认知缺陷的影响。PCP（10mg/kg/天，共10天）诱导的认知缺陷通过随后亚慢性（2周）给予NFPS（1.0和3.0mg/kg/天）或D-丝氨酸（600mg/kg/天）得到显著改善。然而，单次给予NFPS（3.0mg/kg）并不能改善PCP诱导的认知缺陷。此外，蛋白质印迹分析显示，PCP（10mg/kg/天，共10天）处理的小鼠海马体而非额叶皮质中的GlyT-1水平显著高于生理盐水处理的小鼠。一项体内微透析研究显示，反复给予PCP可显著降低小鼠海马体而非额叶皮质中甘氨酸的细胞外水平。这些发现表明，反复给予PCP可增加小鼠脑海马体中GlyT-1的密度，并且GlyT-1抑制剂NFPS可改善反复给予PCP后小鼠的认知缺陷。
