Effect of acute and repeated treatment with mirtazapine on the immunity of noradrenaline transporter knockout C57BL/6J mice

Pathological immunoactivation is thought to play an important role in the etiology of depression; however, the effect of novel antidepressant drugs on immunity has been poorly recognized. Mirtazapine, an antidepressant drug, enhances noradrenergic and serotonergic neurotransmissions, which are crucially involved in the regulation of immune system activity. In the present study we examined the effect of acute and seven-day repeated administration of mirtazapine (20 mg/kg, i.p.) on immunoreactivity in noradrenaline transporter knockout (NET-KO) and wild-type male C57BL/6J mice subjected to the forced swimming test (FST). Mirtazapine decreased immobility time in the FST after acute, but not seven-day repeated, administration to C57BL/6J mice. Lack of the antidepressant effect of mirtazapine was observed, after acute and repeated administration to NET-KO mice, although those mice showed a significantly shorter immobility time in the FST than did wild-type animals. Seven-day repeated mirtazapine administration to wild-type mice suppressed the proliferative activity of splenocytes and their ability to produce pro-inflammatory cytokines, whereas production of IL-4 was stimulated. Acute mirtazapine administration did not change immune parameters in C57BL/6J mice. In NET-KO mice, acute and seven-day repeated mirtazapine administration reduced the proliferative activity of splenocytes and their ability to produce pro-inflammatory cytokines. This study indicates that, in comparison with wild-type C57BL/6J mice, NET-KO mice show enhanced mobility, which is not further potentiated by mirtazapine treatment. Furthermore, the NET-KO mice display higher susceptibility to the immunosuppressive effects of mirtazapine than do the wild-type animals. The present paper postulates an essential role of noradrenergic system in the immunological and behavioral effects of mirtazapine.