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.