Atypical antidepressant mirtazapine inhibits 5-hydroxytryptamine3 receptor currents in NCB-20 cells.

Mirtazapine, an atypical antidepressant, is known to enhance serotonergic transmission by inhibiting the 5-hydroxytryptamine (5-HT), 5-HT, and 5-HT receptors. However, the mechanism of action on the 5-HT receptor remains unclear. We investigated the inhibitory mechanisms of mirtazapine on 5-HT receptors of NCB20 neuroblastoma cells using the whole-cell voltage-clamp method. Mirtazapine inhibited the 5-HT receptor currents in a concentration-dependent manner, and the inhibitory effect was influenced by the concentration of 5-HT. When mirtazapine was co-applied to 5-HT, the maximal response of the 5-HT receptor current was reduced and EC was increased, suggesting that mirtazapine might act as a non-competitive inhibitor. Inhibition of 5-HT current by mirtazapine was stronger in pre-application than in co-application, which suggests that mirtazapine might act as a closed state inhibitor. This finding was further supported by no use-dependency of the mirtazapine for 5-HT receptor inhibition. Finally, mirtazapine accelerated the desensitization and deactivation process in a concentration-dependent manner. The difference in recovery time showed that mirtazapine drastically influences the desensitization process than the deactivation process. These mechanistic characteristics of mirtazapine support the understanding of the relationship between the 5-HT receptor and atypical antidepressants.