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Behavioral/Systems/Cognitive

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 and P. Jeffrey Conn
Journal of Neuroscience 20 August 2003, 23 (20) 7586-7591; https://doi.org/10.1523/JNEUROSCI.23-20-07586.2003
Gene G. Kinney
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486
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Cyrille Sur
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486
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Maryann Burno
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486
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Pierre J. Mallorga
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486
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Jacinta B. Williams
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486
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David J. Figueroa
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486
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Marion Wittmann
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486
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Wei Lemaire
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486
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P. Jeffrey Conn
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486
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  • Figure 1.
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    Figure 1.

    Chemical structure of NFPS (N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl] sarcosine).

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    Figure 2.

    Competition experiments revealed that (+/-)-NFPS and its enantiomers fully antagonized [14C]glycine (10 μm) uptake in HEK-293 cells recombinantly expressing rat GlyT1a with IC50 values shown in Table 1. Similar experiments with rat GlyT2 revealed the subtype selectivity of these compounds. Data are the mean IC50 values ± SEMs from three experiments. Nonspecific uptake was determined in the presence of 10 mm cold glycine. Error bars represent SEMs.

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    Figure 3.

    Photomicrographs illustrating the expression of c-Fos immunoreactivity in nucleus accumbens (NAcc) (left column) and prefrontal cortex (PFC) (right column) of rats treated with vehicle (A, B), (+)-NFPS (10 mg/kg, i.p.) (C, D), and clozapine (20 mg/kg, i.p.) (E, F).

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    Figure 4.

    Group data depicting the effect of (+/-)-NFPS (3 mg/kg, i.v.) administration on LTP in the hippocampal dentate gyrus produced by delivery of a high-frequency electrical stimulation of the perforant path in anesthetized rats. An injection of vehicle or (+/-)-NFPS was administered 30 min after the initiation of each experiment and 30 min before the delivery of the tetanic stimulation. After stimulation of the perforant pathway, NFPS-treated rats displayed a significantly greater magnitude of LTP that was maintained for the duration of the testing period. Data are grouped in 10 min bins, and asterisks represent a significant difference from vehicle-treated rats: *p < 0.05, **p < 0.01. Error bars represent SEMs; n = 10 per group.

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    Figure 5.

    Group data depicting basal PPI in three mouse strains at four prepulse intensities (5-20 dB above background). DBA/2J mice showed significantly lower levels of PPI relative to the 129S6 and C57BL/6 strains. Asterisks represent a significant difference from DBA/2J mice: *p < 0.05, **p < 0.01, ***p < 0.001. Error bars represent SEMs; n = 8 per group.

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    Figure 6.

    A, The effect of vehicle, two doses of NFPS (1 and 10 mg/kg, i.p.), and clozapine (6 mg/kg, i.p.) on PPI in DBA/2J mice at four prepulse intensities (5-20 dB above background). Vehicle and NFPS were administered 120 min before placement in the testing apparatus, whereas clozapine was administered 20 min before testing. Asterisks represent a significant difference from the vehicle group: **p < 0.01, ***p < 0.001. Error bars represent SEMs. B, The effect of vehicle, NFPS, and clozapine on startle amplitude during pulse-alone trials in the same mice represented in A. The asterisk represents a significant difference from the vehicle group: *p < 0.05. Error bars represent SEMs.

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    Table 1.

    Summary of group data for c-Fos studies

    PFC NAcc M Str DL Str
    Control 18 ± 4 19 ± 4 9 ± 1 8 ± 2
    (+)-NFPS 52 ± 10* 80 ± 12** 18 ± 5 13 ± 2
    Clozapine 112 ± 12*** 104 ± 10*** 29 ± 2** 14 ± 1
    • PFC, Prefrontal cortex; NAcc, nucleus accumbens; M Str, medial striatum; DL Str, dorsolateral striatum.

      Data are means ± SEMs from 24 sections per area and 12 sections per area for control and (+)-NFPS rats (n = 4) and clozapine rats (n = 3), respectively.

      ANOVA (p < 0.05) followed by Newman-Keuls multiple comparison test. *p < 0.05; **p < 0.01; ***p < 0.001 versus control.

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The Journal of Neuroscience: 23 (20)
Journal of Neuroscience
Vol. 23, Issue 20
20 Aug 2003
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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, P. Jeffrey Conn
Journal of Neuroscience 20 August 2003, 23 (20) 7586-7591; DOI: 10.1523/JNEUROSCI.23-20-07586.2003

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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, P. Jeffrey Conn
Journal of Neuroscience 20 August 2003, 23 (20) 7586-7591; DOI: 10.1523/JNEUROSCI.23-20-07586.2003
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Keywords

  • glycine
  • schizophrenia
  • c-fos
  • prepulse inhibition
  • long-term potentiation
  • DBA/2J mouse
  • NMDA

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