Anxiolytic effects of mirtazapine microinjection in the median raphe nucleus and subchronic lithium carbonate enhances this effect
摘要：＜正＞Objective Mirtazapine,an antagonist for centralα2-adrenergic autoreceptors and heteroreceptors,and postsynaptic 5-hydroxytryptamine2（5-HT2） and 5-HT3 receptors,achieves its unique therapeutic effect by enhancing noradrenaline and serotonin release,and is effective for the treatment of various anxiety disorders,in addition to depressive disorders.Though preclinical and clinical studies have shown that mirtazapine exerts anxiolytic action,its precise brain target sites remain unclear.Lithium has been mainly used in the treatment of bipolar disorder,but recently,evidence from animal and clinical studies has shown that lithium has an effect on monoamine systems to potentiate the antidepressant action of tricyclic antidepressants, selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors.However, few studies have investigated the effect of lithium with mirtazapine.Previous studies have shown that both lithium and mirtazapine influence serotonergic systems and anxiety.These suggest the possibility that the combination of lithium and mirtazapine may have better efficacies for anxiety disorders. Methods By using contextual fear conditioning test in rats,an animal model of anxiety,we investigated the effects of mirtazapine microinjection into the MRN,hippocampus and amygdala. Furthermore,we examined the effect of subchronic lithium（for 1 week in food） in combination with systemic mirtazapine treatment（i.p.） and local injection of mirtazapine into the median raphe nucleus,hippocampus and amygdala on the expression of contextual conditioned fear. Freezing behavior induced by conditioned fear was analyzed as an index of fear. Results Mirtazapine dose-dependently reduced freezing.Intra-MRN injection of mirtazapine reduced freezing behavior significantly,while injections into the hippocampus or the amygdala did not.Subchronic 0.2%Li2CO3,but not 0.05%Li2CO3,enhanced the inhibitory effect of systemic mirtazapine treatment.Subchronic 0.2%Li2CO3 treatment enhanced the inhibitory effect of local infusion of mirtazapine into the median raphe nucleus,but not hippocampus or amygdala on conditioned freezing. Conclusion These results suggest that the anxiolytic effect of mirtazapine might be mediated by its action on the MRN,and subchronic 0.2%Li2CO3 treatment enhances the anxiolytic-like effect of mirtazapine though the MRN.