Effects of clomipramine on neuronal nicotinic acetylcholine receptors

The action of the tricyclic antidepressant clomipramine on membrane currents elicited by acetylcholine was studied in Xenopus oocytes expressing neuronal alpha2beta4 nicotinic acetylcholine receptors. Clomipramine inhibited the acetylcholine responses rapidly and reversibly, with a similar IC(50) when the oocytes were preincubated with clomipramine (1.3+/-0.2 microM) or when they were exposed simultaneously with acetylcholine and clomipramine (1.5+/-0.3 microM). The EC(50) was 39.9+/-2.1 microM for acetylcholine alone and 65.7+/-3.6 microM for acetylcholine in the presence of 2 microM clomipramine. The inhibitory effect of clomipramine was weakly voltage-dependent, with an electric distance of approximately 0.14. Moreover, clomipramine increased the rate of decay of currents elicited by acetylcholine. From all of these, we conclude that clomipramine reversibly and noncompetitively regulates neuronal alpha2beta4 nicotinic acetylcholine receptors by blocking the open receptor-channel complex at a site close to the extracellular vestibule of the channel. The actions of clomipramine on neuronal nicotinic acetylcholine receptors may play an important role in the treatment of mental depression and other mood disorders.