Noradrenergic antidepressants increase cortical dopamine: potential use in augmentation strategies

Most antidepressant treatments, based on serotonin (5-HT) and/or norepinephrine (NE) transporter blockade, show limited efficacy and slow onset of action, requiring the use of augmentation strategies. Here we report on a novel antidepressant strategy to selectively increase DA function in prefrontal cortex (PFC) without the potential tolerance problems associated to DA transporter blockade. This approach is based on previous observations indicating that extracellular DA in rat medial PFC (mPFC) - but not in nucleus accumbens (NAc) - arises from noradrenergic terminals and is sensitive to noradrenergic drugs. A low dose of reboxetine (3 mg/kg i.p.; NE reuptake inhibitor) non-significantly increased extracellular DA in mPFC. Interestingly, its combined administration with 5 mg/kg s.c. mirtazapine (non-selective α₂-adrenoceptor antagonist) increased extracellular DA in mPFC (264 ± 28%), but not in NAc. Extracellular NE (but not 5-HT) in mPFC was also enhanced by the combined treatment (472 ± 70%). Repeated (×3) reboxetine + mirtazapine administration produced a moderate additional increase in mPFC DA and markedly reduced the immobility time (-51%) in the forced-swim test. Neurochemical and behavioral effects of the reboxetine + mirtazapine combination persisted in rats pretreated with citalopram (3 mg/kg, s.c.), suggesting its potential usefulness to augment SSRI effects. In situ hybridization c-fos studies were performed to examine the brain areas involved in the above antidepressant-like effects, showing changes in c-fos expression in hippocampal and cortical areas. BDNF expression was also increased in the hippocampal formation. Overall, these results indicate a synergistic effect of the reboxetine + mirtazapine combination to increase DA and NE function in mPFC and to evoke robust antidepressant-like responses.