Noradrenaline reuptake inhibition enhances the antipsychotic-like effect of raclopride and potentiates D2-blockage-induced dopamine release in the medial prefrontal cortex of the rat.

We have previously observed that addition of an alpha(2)-adrenoceptor antagonist to a selective dopamine (DA) D(2) receptor antagonist enhances the antipsychotic-like effect of the D(2) blocker and also selectively increases DA output in the medial prefrontal cortex (mPFC) in rats. These data also correlate well with previous clinical trials showing augmentation by an equivalent drug combination in schizophrenia. Since the selective noradrenaline reuptake inhibitor reboxetine was found to cause similar effects on the mesolimbocortical DA system as alpha(2)-adrenoceptor antagonists, the present study was undertaken to explore whether also reboxetine might augment the effect of the DA D(2) receptor antagonist raclopride in the same preclinical model of antipsychotic activity, the conditioned avoidance response (CAR) test. We also investigated the effect of this combination in the catalepsy test for extrapyramidal side effect liability, as well as on DA output in the mPFC and the nucleus accumbens, respectively. Reboxetine (6 mg/kg, i.p.) significantly enhanced the suppressant effect of raclopride (0.1 mg/kg, s.c.) on CAR without affecting catalepsy. Administration of raclopride (0.1 mg/kg, s.c.) to rats pretreated with reboxetine (6 mg/kg, i.p.) resulted in a greatly enhanced effect on DA output in the mPFC but not in the nucleus accumbens when compared with raclopride alone. Consequently, these results suggest that noradrenaline reuptake inhibition may provide means of augmenting the efficacy of classical D(2)-antagonists in the treatment of schizophrenia, and, in principle, to generate an atypical antipsychotic drug profile.