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Research ArticleBehavioral Pharmacology

Effects of a Positive Allosteric Modulator of Group II Metabotropic Glutamate Receptors, LY487379, on Cognitive Flexibility and Impulsive-Like Responding in Rats

Agnieszka Nikiforuk, Piotr Popik, Karla U. Drescher, Marcel van Gaalen, Ana-Lucia Relo, Mario Mezler, Gerard Marek, Hans Schoemaker, Gerhard Gross and Anton Bespalov
Journal of Pharmacology and Experimental Therapeutics December 2010, 335 (3) 665-673; DOI: https://doi.org/10.1124/jpet.110.170506
Agnieszka Nikiforuk
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Piotr Popik
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Karla U. Drescher
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Marcel van Gaalen
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Ana-Lucia Relo
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Mario Mezler
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Gerard Marek
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Hans Schoemaker
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Gerhard Gross
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Anton Bespalov
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Abstract

Orthosteric group II metabotropic glutamate receptor (mGluR) agonists are regarded as novel, effective medications for all major symptom domains of schizophrenia, including cognitive disturbances. mGluR2s also can be affected in a more subtle way by positive allosteric modulators (PAMs) characterized by a unique degree of subtype selectivity and neuronal frequency-dependent activity. Because currently available treatments for schizophrenia do not improve cognitive dysfunction, the main aim of the present study was to examine the effects of a mGluR2 PAM, N-(4-(2-methoxyphenoxy)-phenyl-N-(2,2,2-trifluoroethylsulfonyl)-pyrid-3-ylmethylamine (LY487379), on rat cognitive flexibility and impulsive-like responding, assessed in an attentional set-shifting task (ASST) and a differential reinforcement of low-rate 72 s (DRL72) schedule of food reinforcement. In addition, in vivo microdialysis was used to assess the drug's impact on cortical levels of dopamine, norepinephrine, serotonin, and glutamate. Rats treated with LY487379 (30 mg/kg) required significantly fewer trials to criteria during the extradimensional shift phase of the ASST. Under a DRL72 schedule, LY487379 (30 mg/kg) decreased the response rate and increased the number of reinforcers obtained. These effects were accompanied by the shift of the frequency distribution of responses toward longer inter-response time durations. LY487379 significantly enhanced extracellular norepinephrine and serotonin levels in the medial prefrontal cortex. In summary, the present study demonstrates that a mGluR2 PAM, LY487379, promotes cognitive flexibility and facilitates behavioral inhibition. These procognitive effects may contribute to the therapeutic efficacy of agents stimulating mGluR2 in schizophrenia.

Footnotes

  • These studies were funded by Abbott.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.170506.

  • ABBREVIATIONS:

    mGluR
    metabotropic glutamate receptor
    5-HT
    5-hydroxytryptamine
    ANOVA
    analysis of variance
    ASST
    attentional set-shifting task
    CD
    compound discrimination
    DRL72
    differential reinforcement of low-rate 72 s
    ED
    extradimensional
    ID
    intradimensional
    IRT
    inter-response time
    mPFC
    medial prefrontal cortex
    NMDA
    N-methyl-d-aspartate
    NMDAR
    NMDA receptor
    PAM
    positive allosteric modulator
    PCP
    phencyclidine
    Rev 1
    first reversal
    Rev 2
    second reversal
    Rev 3
    third reversal
    SD
    simple discrimination
    SSRI
    selective serotonin reuptake inhibitor
    n.s.
    not significant
    LY487379
    N-(4-(2-methoxyphenoxy)-phenyl-N-(2,2,2-trifluoroethylsulfonyl)-pyrid-3-ylmethylamine
    LY354740
    (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid
    LY379268
    (−)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid
    LY404039
    (−)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid.

  • Received May 21, 2010.
  • Accepted August 18, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 377 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 377, Issue 2
1 May 2021
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Research ArticleBehavioral Pharmacology

Effects of a Positive Allosteric Modulator of Group II Metabotropic Glutamate Receptors, LY487379, on Cognitive Flexibility and Impulsive-Like Responding in Rats

Agnieszka Nikiforuk, Piotr Popik, Karla U. Drescher, Marcel van Gaalen, Ana-Lucia Relo, Mario Mezler, Gerard Marek, Hans Schoemaker, Gerhard Gross and Anton Bespalov
Journal of Pharmacology and Experimental Therapeutics December 1, 2010, 335 (3) 665-673; DOI: https://doi.org/10.1124/jpet.110.170506

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Research ArticleBehavioral Pharmacology

Effects of a Positive Allosteric Modulator of Group II Metabotropic Glutamate Receptors, LY487379, on Cognitive Flexibility and Impulsive-Like Responding in Rats

Agnieszka Nikiforuk, Piotr Popik, Karla U. Drescher, Marcel van Gaalen, Ana-Lucia Relo, Mario Mezler, Gerard Marek, Hans Schoemaker, Gerhard Gross and Anton Bespalov
Journal of Pharmacology and Experimental Therapeutics December 1, 2010, 335 (3) 665-673; DOI: https://doi.org/10.1124/jpet.110.170506
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