%0 Journal Article %A Eunice Y Yuen %A Xiangning Li %A Jing Wei %A Masakuni Horiguchi %A Herbert Y Meltzer %A Zhen Yan %T The Novel Antipsychotic Drug Lurasidone Enhances NMDA Receptor-Mediated Synaptic Responses %D 2011 %R 10.1124/mol.111.076141 %J Molecular Pharmacology %P mol.111.076141 %X 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 (trade name Latuda), 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 the surface expression of NR2A and NR2B subunits. Lurasidone has high affinity for serotonin 5-HT1A, 5-HT2A, 5-HT7 receptors and dopamine D2 receptors. In vivo administration of the 5-HT7 receptor antagonist SB-269970 mimicked the enhancing effect of lurasidone on NMDAR responses, while the D2 receptor antagonist haloperidol failed to do so. Previous studies have found that acute 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 the normal level 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. %U https://molpharm.aspetjournals.org/content/molpharm/early/2011/11/09/mol.111.076141.full.pdf