RT Journal Article
SR Electronic
T1 The Novel Antipsychotic Drug Lurasidone Enhances <em>N</em>-Methyl-<span class="sc">d</span>-aspartate Receptor-Mediated Synaptic Responses
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 113
OP 119
DO 10.1124/mol.111.076141
VO 81
IS 2
A1 Yuen, Eunice Y.
A1 Li, Xiangning
A1 Wei, Jing
A1 Horiguchi, Masakuni
A1 Meltzer, Herbert Y.
A1 Yan, Zhen
YR 2012
UL http://molpharm.aspetjournals.org/content/81/2/113.abstract
AB 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.