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, Zhen Yan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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-HT 1A, 5-HT 2A, and 5-HT 7 receptors and dopamine D 2 receptors. In vivo administration of the 5-HT 7 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 D 2 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-HT 7 receptors, which is consistent with evidence that 5-HT 7 receptor antagonism contributes to cognitive enhancement by atypical APDs in patients with schizophrenia.

Original languageEnglish (US)
Pages (from-to)113-119
Number of pages7
JournalMolecular pharmacology
Volume81
Issue number2
DOIs
StatePublished - Feb 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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