title: The novel antipsychotic drug lurasidone enhances N-methyl-D-aspartate receptor-mediated synaptic responses.
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.
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York 14214, USA.
authors.forename: Eunice Y
authors.initials: EY
authors.lastname: Yuen
authors.forename: Xiangning
authors.initials: X
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.forename: Masakuni
authors.initials: M
authors.lastname: Horiguchi
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents; D003024:Clozapine / Q000494:pharmacology / Q000627:therapeutic use; D003072:Cognition Disorders / Q000209:etiology; D004195:Disease Models, Animal; D054833:Isoindoles / Q000494:pharmacology* / Q000627:therapeutic use; D000069056:Lurasidone Hydrochloride; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy; D009435:Synaptic Transmission / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D014150:Antipsychotic Agents; D054833:Isoindoles; D044402:Receptor, Serotonin, 5-HT2A; D016194:Receptors, N-Methyl-D-Aspartate; D013844:Thiazoles; D003024:Clozapine; D000069056:Lurasidone Hydrochloride
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