Role of concomitant inhibition of the norepinephrine transporter for the antipsychotic effect of quetiapine

Quetiapine alleviates both positive and negative symptoms as well as certain cognitive impairments in schizophrenia despite a low D2 receptor occupancy and may also be used as monotherapy in bipolar and major depressive disorder. The mechanisms underlying the broad clinical utility of quetiapine remain to be clarified, but may be related to the potent inhibition of the norepinephrine transporter (NET) by norquetiapine, the major metabolite of quetiapine in humans. Since norquetiapine is not formed in rodents we here investigated in rats whether NET-inhibition may, in principle, contribute to the clinical effectiveness of quetiapine and allow for its low D2 receptor occupancy, by combining quetiapine with the selective NET-inhibitor reboxetine. Antipsychotic-like activity was assessed using the conditioned avoidance response (CAR) test, dopamine output in the medial prefrontal cortex (mPFC) and the nucleus accumbens was measured using in vivo microdialysis, and NMDA receptor-mediated transmission was measured using intracellular electrophysiological recordings in pyramidal cells of the mPFC in vitro. Adjunct reboxetine potentiated the suppression of CAR by quetiapine. Moreover, concomitant administration of quetiapine and reboxetine resulted in a synergistic increase in cortical, but not accumbal, dopamine output. The combination of low, clinically relevant concentrations of quetiapine (60 nM) and reboxetine (20 nM) markedly facilitated cortical NMDA receptor-mediated transmission in contrast to either drug alone, an effect that could be inhibited by the D1 receptor antagonist SCH23390. We conclude that concomitant NET-inhibition by norquetiapine may contribute to the overall antipsychotic effectiveness of quetiapine in spite of its relatively low level of D2 occupancy.