Sertindole restores attentional performance and suppresses glutamate release induced by the NMDA receptor antagonist CPP

Abstract

Blockade of N-methyl-d-aspartic acid (NMDA) receptors in the rat medial prefrontal cortex (mPFC) impairs performance in the five-choice serial reaction time task (5-CSRTT) and increases glutamate (GLU) release. Recent research suggests that excessive GLU release may be critical for attention deficits. We tested this hypothesis by investigating the effects of the atypical antipsychotics sertindole and clozapine on 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP)-induced performance deficits in the 5-CSRTT and on the CPP-induced GLU release in the mPFC. The 5-CSRTT, a test of divided and sustained visual attention providing indices of attentional functioning (accuracy of visual discrimination), response control (anticipatory and perseverative responses) and intracortical microdialysis in conscious rats were used to investigate the effects of sertindole and clozapine. Low doses of sertindole (0.02-0.32mg/kg) prevented CPP-induced accuracy deficits, anticipatory over-responding and the rise in GLU release. In contrast, doses ranging from 0.6 to 2.5mg/kg had no effect or even enhanced the effect of CPP on anticipatory responding. Similarly, 2.5mg/kg sertindole was unable to reverse CPP-induced rise in GLU release. Clozapine (2.5mg/kg) prevented accuracy deficits and the increase in anticipatory responding and abolished the rise in GLU release induced by CPP. These findings show that the ameliorating effects of sertindole and clozapine on NMDA receptor dependent attention deficit is associated with suppression in GLU release in the mPFC. This supports the proposal that suppression in GLU release might be a target for the development of novel drugs aimed at counteracting some aspects of cognitive deficits of schizophrenia.