Comparative study of the effects of desipramine and reboxetine on locus coeruleus neurons in rat brain slices

Several studies have suggested that the locus coeruleus may play an important role in the pathophysiology of depression. The aim of this study was to characterize, using single-unit extracellular recordings, the in vitro effects of the noradrenaline reuptake inhibitors desipramine and reboxetine, on locus coeruleus neurons from control rats and from those chronically treated with desipramine. Bath application of desipramine (1–100 μM) and reboxetine (0.1–10 μM) decreased the firing rate of locus coeruleus neurons in a concentration-dependent manner and the α2-adrenoceptor antagonist RX 821002 (10 μM) reversed these effects. In addition, reserpine (5 mg/kg, 3 h before the experiment) almost completely blocked the inhibitory effect of desipramine. Both drugs (1 μM desipramine and 0.1 μM reboxetine) potentiated the inhibitory effect of noradrenaline (10 μM). A 7-day treatment with desipramine (3 mg/kg/12 h, i.p.) caused a decrease in sensitivity to the α2-adrenoceptor agonist bromoxidine (EC50 increased by 3.3-fold), but not to noradrenaline or reboxetine. In contrast, this treatment potentiated the inhibitory effect of desipramine with respect to control. Moreover, 14-day treatment with desipramine (3 mg/kg/12 h, i.p.) or reboxetine (10 mg/kg/12 h, i.p.) also potentiated the in vitro effect of desipramine without modifying the in vitro effect of reboxetine. These results show that desipramine and reboxetine modulate the activity of locus coeruleus neurons by noradrenaline acting on α2-adrenoceptors, and reveal that α2-adrenoceptor-independent mechanisms may also underlie the action of noradrenaline uptake inhibitors.