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

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• 作者：Grandoso ; Laura ; Pineda ; Joseba ; Ugedo ; Luisa
• 关键词：Desipramine ; Reboxetine ; Locus coeruleus ; α ; ₂-Adrenoceptor desensitization ; Antidepressant
• 刊名：Neuropharmacology
• 出版年：2004
• 出版时间：May, 2004
• 年：2004
• 卷：46
• 期：6
• 页码：815-823
• 全文大小：211 K

文摘

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.