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The Journal of Neuroscience, August 20, 2003, 23(20):7586-7591
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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
Gene G. Kinney, * Cyrille Sur, * Maryann Burno, Pierre J. Mallorga, Jacinta B. Williams, David J. Figueroa, Marion Wittmann, Wei Lemaire, andP. Jeffrey Conn Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486
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.
Key words: glycine; schizophrenia; c-Fos; prepulse inhibition; long-term potentiation; DBA/2J mouse; NMDA
Received May. 8, 2003; revised Jun. 13, 2003; accepted Jun. 18, 2003.
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