Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission

Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D2/3 antagonist raclopride and, in parallel, enhances cortical dopamine output. Subsequent clinical results suggested that adding reboxetine to stable treatments with various antipsychotic drugs (APDs) may improve positive, negative and depressive symptoms in schizophrenia. In this study, we investigated in rats the effects of adding reboxetine to the second-generation APD olanzapine on: (i) antipsychotic efficacy, using the conditioned avoidance response (CAR) test, (ii) extrapyramidal side effect (EPS) liability, using a catalepsy test, (iii) dopamine efflux in the medial prefrontal cortex and the nucleus accumbens, using in vivo microdialysis in freely moving animals and (iv) cortical N-methyl--aspartate (NMDA) receptor-mediated transmission, using intracellular electrophysiological recording in vitro. Reboxetine (6 mg/kg) enhanced the suppression of CAR induced by a suboptimal dose (1.25 mg/kg), but not an optimal (2.5 mg/kg) dose of olanzapine without any concomitant catalepsy. Addition of reboxetine to the low dose of olanzapine also markedly increased cortical dopamine outflow and facilitated prefrontal NMDA receptor-mediated transmission. Our data suggest that adjunctive treatment with a NET inhibitor may enhance the therapeutic effect of low-dose olanzapine in schizophrenia without increasing EPS liability and add an antidepressant action, thus in principle allowing for a dose reduction of olanzapine with a concomitant reduction of dose-related side effects, such as EPS and weight gain

Olanzapine Sensitization and Clozapine Tolerance: From Adolescence to Adulthood in the Conditioned Avoidance Response Model

Disruption of conditioned avoidance response (CAR) in rodents is one trademark feature of many antipsychotic drugs. In adult rats, repeated olanzapine (OLZ) treatment causes an enhanced disruption of avoidance response (sensitization), whereas repeated clozapine (CLZ) treatment causes a decreased disruption (tolerance). The present study addressed (1) whether OLZ sensitization and CLZ tolerance can be induced in adolescent rats, and (2) the extent to which OLZ sensitization and CLZ tolerance induced in adolescence persists into adulthood. Male adolescent Sprague–Dawley rats (approximate postnatal days (BP) 43–47) were first treated with OLZ (1.0 or 2.0 mg/kg, subcutaneously (sc)) or CLZ (10 or 20 mg/kg, sc) daily for 5 consecutive days in the CAR model. They were then tested for the expression of OLZ sensitization or CLZ tolerance either in adolescence (BP 50) or after they matured into adults (BP 76 and 92) in a challenge test during which all rats were injected with either a lower dose of OLZ (0.5 mg/kg) or CLZ (5.0 mg/kg). When tested in adolescence, rats previously treated with OLZ showed a stronger inhibition of CAR than those previously treated with vehicle (ie, sensitization). In contrast, rats previously treated with CLZ showed a weaker inhibition of CAR than those previously treated with vehicle (ie, tolerance). When tested in adulthood, the OLZ sensitization was still detectable at both time points (BP 76 and 92), whereas the CLZ tolerance was only detectable on BP 76, and only manifested in the intertrial crossing. Performance in the prepulse inhibition and fear-induced 22 kHz ultrasonic vocalizations in adulthood were not altered by adolescence drug treatment. Collectively, these findings suggest that atypical antipsychotic treatment during adolescence can induce a long-term specific alteration in antipsychotic effect that persists into adulthood despite the brain maturation. As antipsychotic drugs are being increasingly used in children and adolescents in the past two decades, findings from this study are important for understanding the impacts of adolescent antipsychotic treatment on the brain and behavioral developments. This work also has implications for clinical practice involving adolescence antipsychotic treatments in terms of drug choice, drug dose, and schedule