Reboxetine enhances the antipsychotic-like effect of olanzapine and facilitates cortical dopaminergic and NMDA receptor-mediated transmission in analogy with clozapine.

Abstract

Preclinical data show that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine to raclopride, a typical D2/3 antagonist, increases its antipsychotic efficacy and, in parallel, enhances dopamine output in the medial prefrontal cortex (mPFC), effects similar to those of clozapine. Subsequent clinical results suggest that adding reboxetine to a stable treatment with various antipsychotic drugs (APDs) may indeed improve positive, negative and depressive symptoms in schizophrenia. Here we investigated in rats the effects of concomitant administration of reboxetine and the second generation APD olanzapine on: i) antipsychotic effect using the conditioned avoidance response (CAR) test, ii) extrapyramidal side effect (EPS) liability using the catalepsy test, iii) dopamine efflux in the mPFC and the nucleus accumbens using in vivo microdialysis in freely moving animals, and iv) cortical NMDA receptor-mediated transmission using intracellular electrophysiological recording in vitro. Reboxetine (6 mg/kg) enhanced the suppression of CAR induced by a low (1.25 mg/kg), but not a high (2.5 mg/kg) dose of olanzapine without any concomitant catalepsy. Addition of reboxetine to the low dose of olanzapine also induced a large increase in cortical dopamine outflow as well as a markedly enhanced NMDA receptor-mediated transmission, in analogy with clozapine. These data help explain how adjunctive treatment with a NET inhibitor may enhance the efficacy of olanzapine in schizophrenia, yet without increasing EPS liability, including an antidepressant action, and allow for a reduction of dosage as well as dose-related side effects such as weight gain, which has already been observed clinically.