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Molecular Pharmacology

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Rapid CommunicationAccelerated Communication

The Novel Antipsychotic Drug Lurasidone Enhances N-Methyl-d-aspartate Receptor-Mediated Synaptic Responses

Eunice Y. Yuen, Xiangning Li, Jing Wei, Masakuni Horiguchi, Herbert Y. Meltzer and Zhen Yan
Molecular Pharmacology February 2012, 81 (2) 113-119; DOI: https://doi.org/10.1124/mol.111.076141
Eunice Y. Yuen
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Xiangning Li
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Jing Wei
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Masakuni Horiguchi
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Herbert Y. Meltzer
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Zhen Yan
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Abstract

N-Methyl-d-aspartate (NMDA) receptor (NMDAR) hypofunction has been postulated to contribute to the cognitive deficit of schizophrenia. In this study, we examined the effect of lurasidone (Latuda; Dainippon Sumitomo Pharma Co. Ltd., Tokyo, Japan), a newly approved atypical antipsychotic drug (APD), on NMDAR synaptic function in rat frontal cortical pyramidal neurons. In vivo administration of lurasidone produced a significant and selective enhancement of NMDAR-mediated synaptic responses and surface expression of NR2A and NR2B subunits. Lurasidone has high affinity for serotonin 5-HT1A, 5-HT2A, and 5-HT7 receptors and dopamine D2 receptors. In vivo administration of the 5-HT7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2 -(2-(4-methyl-1-piperidinyl)ethyl)pyrrolidine (SB-269970) mimicked the enhancing effect of lurasidone on NMDAR responses, whereas the D2 receptor antagonist haloperidol failed to do so. Previous studies have found that short-term administration of lurasidone reverses the cognitive impairment induced by subchronic administration of phencyclidine (PCP), an NMDAR noncompetitive antagonist. In this study, we found that lurasidone, as well as the prototypical atypical APD clozapine, restored NMDAR-mediated synaptic responses to normal levels in the PCP model of schizophrenia. These results suggest that NMDAR is the potential key molecular target of lurasidone, possibility via antagonizing 5-HT7 receptors, which is consistent with evidence that 5-HT7 receptor antagonism contributes to cognitive enhancement by atypical APDs in patients with schizophrenia.

Footnotes

  • This work was supported by grants from the National Institutes of Health National Institute on Mental Health [Grants MH84233, MH55441] (to Z.Y.).

  • H.Y.M. is a stockholder of ACADIA, Astra Zeneca, and SureGene and has received grant support in the last 3 years from BioLine Rx, Cephalon, Dainippon Sumitomo, Eli Lilly, EnVivo, Janssen, Otsuka, Pfizer, and Sunovion. He is, or has been, a consultant to ACADIA, Alkemes, Astellas, Boehringer Mannheim, Bristol Myers Squibb, Cypress, Janssen, Lundbeck, Ovation, Merck, Novartis, Pfizer, Teva, and Valeant (BioVail).

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

    http://dx.doi.org/10.1124/mol.111.076141.

  • ABBREVIATIONS:

    PFC
    prefrontal cortex
    NMDA
    N-methyl-d-aspartate
    NMDAR
    N-methyl-d-aspartate receptor
    PCP
    phencyclidine
    MK-801
    5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate)
    APD
    antipsychotic drug
    NOR
    novel object recognition
    SB-269970
    (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2 -(2-(4-methyl-1-piperidinyl)ethyl)pyrrolidine
    ACSF
    artificial cerebrospinal fluid
    EPSC
    excitatory postsynaptic current
    mEPSC
    miniature excitatory postsynaptic current
    AMPA
    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
    AMPAR
    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor.

  • Received October 3, 2011.
  • Accepted November 9, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (2)
Molecular Pharmacology
Vol. 81, Issue 2
1 Feb 2012
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Rapid CommunicationAccelerated Communication

Regulation of NMDA Receptors by Lurasidone

Eunice Y. Yuen, Xiangning Li, Jing Wei, Masakuni Horiguchi, Herbert Y. Meltzer and Zhen Yan
Molecular Pharmacology February 1, 2012, 81 (2) 113-119; DOI: https://doi.org/10.1124/mol.111.076141

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Rapid CommunicationAccelerated Communication

Regulation of NMDA Receptors by Lurasidone

Eunice Y. Yuen, Xiangning Li, Jing Wei, Masakuni Horiguchi, Herbert Y. Meltzer and Zhen Yan
Molecular Pharmacology February 1, 2012, 81 (2) 113-119; DOI: https://doi.org/10.1124/mol.111.076141
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