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
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
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DOI：
10.1523/jneurosci.23-20-07586.2003
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发表时间：
2003-08
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通讯作者：
Gene G. Kinney;C. Sur;M. Burno;Pierre J. Mallorga;Jacinta B. Williams;David J. Figueroa;M. Wittmann;Wei Lemaire;P. Jeffrey Conn
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文献类型：
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作者：
Gene G. Kinney;C. Sur;M. Burno;Pierre J. Mallorga;Jacinta B. Williams;David J. Figueroa;M. Wittmann;Wei Lemaire;P. Jeffrey Conn
甘氨酸通过与NR 1亚基上士的宁不敏感的甘氨酸-B结合位点结合，在NMDA受体（NMDAR）复合物中充当谷氨酸的必需促凝剂。甘氨酸在脑和脊髓中的浓度通常超过使该位点饱和所需的浓度，这一事实导致了甘氨酸在体内通常使含NMDAR的突触饱和的推测。然而，额外的证据表明，突触甘氨酸可以有效地调节突触区的甘氨酸转运蛋白1型（GlyT 1）。最近描述的一种有效的和选择性的GlyT 1抑制剂（N-[3-（4 ′-氟苯基）-3-（4′-苯基苯氧基）丙基]肌氨酸[NFPS]）提供了一种工具，用于评估抑制GlyT 1可能增加突触甘氨酸，从而增强体内NMDAR功能的假设。在本研究中，我们发现（+）-NFPS在体外功能性甘氨酸再摄取测定中表现出比外消旋化合物高>10倍的活性。在体内，（+/-）-NFPS显着增强海马齿状回的长时程增强由高频电刺激的传入穿通通路。此外，（+）-NFPS诱导的c-Fos免疫反应模式与非典型抗精神病药物氯氮平和增强的前脉冲抑制的DBA/2 J小鼠的声惊吓反应，一个菌株与低基础水平的前脉冲抑制。总的来说，这些数据表明，选择性抑制GlyT 1可以增强体内NMDAR敏感活性，也支持GlyT 1可能代表开发治疗与NMDAR功能减退相关疾病的新靶点的想法。
Glycine acts as a necessary coagonist for glutamate at the NMDA receptor (NMDAR) complex by binding to the strychnine-insensitive glycine-B binding site on the NR1 subunit. The fact that glycine is normally found in the brain and spinal cord at concentrations that exceed those required to saturate this site has led to the speculation that glycine normally saturates NMDAR-containing synapses in vivo. However, additional lines of evidence suggest that synaptic glycine may be efficiently regulated in synaptic areas by the glycine transporter type 1 (GlyT1). The recent description of a potent and selective GlyT1 inhibitor (N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine [NFPS]) provides a tool for evaluation of the hypothesis that inhibition of GlyT1 may increase synaptic glycine and thereby potentiate NMDAR function in vivo. In the present study, we found that (+)-NFPS demonstrated >10-fold greater activity in an in vitro functional glycine reuptake assay relative to the racemic compound. In vivo, (+/-)-NFPS significantly enhanced long-term potentiation in the hippocampal dentate gyrus induced by high-frequency electrical stimulation of the afferent perforant pathway. Furthermore, (+)-NFPS induced a pattern of c-Fos immunoreactivity comparable with the atypical antipsychotic clozapine and enhanced prepulse inhibition of the acoustic startle response in DBA/2J mice, a strain with low basal levels of prepulse inhibition. Collectively, these data suggest that selective inhibition of GlyT1 can enhance NMDAR-sensitive activity in vivo and also support the idea that GlyT1 may represent a novel target for developing therapeutics to treat disorders associated with NMDAR hypofunction.