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

Abstract

Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D 2/3 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-D-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.

Effects of iloperidone, combined with desipramine, on alcohol drinking in the Syrian golden hamster

“…Moreover, in this model, the addition of IDAZ enhanced the antipsychotic effects of risperidone, facilitated dopaminergic and glutamatergic neurotransmission, and allowed a lower dose of risperidone to achieve maximal effect (Marcus et al, 2010b). Consistent with the findings here, the addition of the NE reuptake inhibitor, reboxetine, to olanzapine (another atypical antipsychotic) also enhanced olanzapine's antipsychotic effects as well as glutamatergic and dopaminergic neurotransmission (Marcus et al, 2010a). Since CLOZ can also directly modulate glutamatergic circuitry (Heresco-Levy, 2003), we will explore the potential role of these mechanisms in mediating CLOZ's effects on alcohol drinking future studies, as well as the potential combination of ILOP with glutamatergic agents to achieve a CLOZ-like effect.…”

Dopamine, the antipsychotic molecule: A perspective on mechanisms underlying antipsychotic response variability

“…Specifically, augmentation with antidepressants has been shown to improve the efficacy of antipsychotics for positive (Joffe et al, 2009;Terevnikov et al, 2010;Terevnikov et al, 2011), negative (Raedler et al, 2004;Singh et al, 2010) and cognitive symptoms (Stenberg et al, 2010;Vernon et al, 2014). Although a double blind placebo-controlled study could not confirm these effects (Usall et al, 2014), observations linking the beneficial effects of monoamine releasers co-administered with antipsychotics are largely in line with data obtained using animal models (Bjorkholm et al, 2015;Marcus et al, 2010;Marcus et al, 2012).…”

The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits, biochemical changes, and hippocampal synaptic plasticity in an animal model of depression

“…RB has been shown to increase the burst‐firing pattern of ventral tegmentum area DA neurons and to increase DA release in the prefrontal cortex (Linner et al, ). Recent studies also showed increased DA outflow in the prefrontal cortex and other regions after treatment with RB (Marcus et al, ; Masana et al, ).…”