Effects of the antidepressant mirtazapine and zinc on nicotinic acetylcholine receptors

摘要

Nicotinic acetylcholine receptors (nAChRs) and zinc are associated with regulation of mood and related disorders. In addition, several antidepressants inhibit muscle and neuronal nAChRs and zinc potentiates inhibitory actions of them. Moreover, mirtazapine (a noradrenergic, serotonergic and histaminergic antidepressant) inhibits muscarinic AChRs and its effects on nAChRs are unknown. Therefore, we studied the modulation of muscle alpha 1 beta 1 gamma d nAChRs expressed in oocytes and native alpha 7-containing nAChRs in hippocampal interneurons by mirtazapine and/or zinc, using voltage-clamp techniques. The currents elicited by ACh in oocytes (at -60 mV) were similarly inhibited by mirtazapine in the absence and presence of 100 mu M zinc (IC50 similar to 15 mu M); however, the ACh-induced currents were stronger inhibited with 20 and 50 mu M mirtazapine in the presence of zinc. Furthermore, the potentiation of ACh-induced current by zinc in the presence of 5 mu M mirtazapine was 1.48 +/- 0.06, and with 50 mu M mirtazapine zinc potentiation did not occur. Interestingly, in stratum radiatum interneurons (at -70 mV), 20 mu M mirtazapine showed less inhibition of the current elicited by choline (Ch) than at 10 mu M (0.81 +/- 0.02 and 0.74 +/- 0.02 of the Ch-induced current, respectively). Finally, the inhibitory effects of mirtazapine depended on membrane potential: 0.81 +/- 0.02 and 0.56 +/- 0.05 of the control Ch-induced current at -70 and -20 mV, respectively. These results indicate that mirtazapine interacts with muscle and neuronal nAChRs, possibly into the ion channel; that zinc may increase the sensitivity of nAChRs to mirtazapine; and that mirtazapine decreases the sensitivity of nAChRs to zinc.