Effects of asenapine on prefrontal NMDA receptor-mediated transmission. Involvement of dopamine D1 receptors

Abstract

Asenapine is a novel psychopharmacologic agent developed for the treatment of schizophrenia and bipolar disorder. In our preclinical experiments, asenapine exhibited a potent antipsychotic effect in doses that did not cause catalepsy. In similarity with clozapine, asenapine also facilitated cortical dopaminergic and glutamatergic neurotransmission and, moreover, the facilitating effect of clozapine on NMDA-induced currents in cortical pyramidal cells can be blocked by the D₁ receptor-antagonist SCH23390. Previously, we have observed that clozapine can both prevent and reverse the phencyclidine-induced block of NMDA-induced currents. Using intracellular recording in vitro, we have now investigated the involvement of D₁ receptor activation in asenapine’s facilitating effect on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex (mPFC). We have also explored asenapine’s capability to reverse the phencyclidine-induced block of these currents. The facilitating effect of asenapine was indeed blocked by the D₁ receptor antagonist SCH23390 and, moreover, asenapine markedly reversed the phencyclidine-induced blockade of these currents. These results demonstrate that the facilitating effect of asenapine on NMDA-induced currents involves activation of D₁ receptors in the mPFC and, combined with previous findings, also indicate that asenapine and clozapine share a common property in reversing phencyclidine-induced hypoactivity of NMDA receptors and associated cognitive deficits by means of a D₁ receptor mediated mechanism. Thus, the ability to increase both dopaminergic and prefrontal cortical NMDA receptor-mediated neurotransmission propose that asenapine may have an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms.