Antagonism of nicotinic acetylcholine receptors by inhibitors of monoamineuptake

A study was made of the effects of several monoamine-uptake inhibitors on m embrane currents elicited by acetylcholine (ACh-currents) generated by rat neuronal alpha2 beta4 and mouse muscle nicotinic acetylcholine receptors (A ChRs) expressed in Xenopus laevis oocytes. For the two types of receptors t he monoamine-uptake inhibitors reduced the ACh-currents albeit to different degrees. The order of inhibitory potency was norfluoxetine > clomipramine > indatraline > fluoxetine > imipramine > zimelidine > 6-nitro-quipazine > trazodone for neuronal alpha2 beta4 AChRs, and norfluoxetine > fluoxetine > imipramine > clomipramine > indatraline > zimelidine > trazodone > 6-nitro -quipazine for muscle AChRs. Thus, the most potent inhibitor was norfluoxet ine, whilst the weakest ones were trazodone, 6-nitro-quipazine and zimelidi ne. Effects of the tricyclic antidepressant imipramine were studied in more detail. Imipramine inhibited reversibly and non-competitively the ACh-curr ent with a similar inhibiting potency for both neuronal alpha2 beta4 and mu scle AChRs. The half-inhibitory concentrations of imipramine were 3.65 +/- 0.30 muM for neuronal alpha2 beta4 and 5.57 +/- 0.19 muM for muscle recepto rs. The corresponding Hill coefficients were 0.73 and 1.2 respectively. The inhibition of imipramine was slightly voltage-dependent, with electric dis tances of similar to0.10 and similar to0.12 for neuronal alpha2 beta4 and m uscle AChRs respectively. Moreover, imipramine accelerated the rate of deca y of ACh-currents of both muscle and neuronal AChRs. The ACh-current inhibi tion was stronger when oocytes, expressing neuronal alpha2 beta4 or muscle receptors, were preincubated with imipramine alone than when it was applied after the ACh-current had been generated, suggesting that imipramine acts also on non-activated or closed AChRs. We conclude that monoamine-uptake in hibitors reduce ACh-currents and that imipramine regulates reversibly and n oncompetitively neuronal alpha2 beta4 and muscle AChRs through similar mech anisms, perhaps by interacting externally on a non-conducting state of the AChR and by blocking the open receptor-channel complex close to the vestibu le of the channel. These studies may be important for understanding the reg ulation of AChRs as well as for understanding antidepressant- and side-effe cts of monoamine-uptake inhibitors.