Abstract
A study was made of the effects of several monoamine-uptake inhibitors on membrane currents elicited by acetylcholine (ACh-currents) generated by rat neuronal α2β4 and mouse muscle nicotinic acetylcholine receptors (AChRs) expressed in Xenopus laevis oocytes. For the two types of receptors the 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 α2β4 AChRs, and norfluoxetine > fluoxetine > imipramine > clomipramine > indatraline > zimelidine > trazodone > 6-nitro-quipazine for muscle AChRs. Thus, the most potent inhibitor was norfluoxetine, whilst the weakest ones were trazodone, 6-nitro-quipazine and zimelidine. Effects of the tricyclic antidepressant imipramine were studied in more detail. Imipramine inhibited reversibly and non-competitively the ACh-current with a similar inhibiting potency for both neuronal α2β4 and muscle AChRs. The half-inhibitory concentrations of imipramine were 3.65 ± 0.30 μM for neuronal α2β4 and 5.57 ± 0.19 μM for muscle receptors. The corresponding Hill coefficients were 0.73 and 1.2 respectively. The inhibition of imipramine was slightly voltage-dependent, with electric distances of ˜0.10 and ˜0.12 for neuronal α2β4 and muscle AChRs respectively. Moreover, imipramine accelerated the rate of decay of ACh- currents of both muscle and neuronal AChRs. The ACh-current inhibition was stronger when oocytes, expressing neuronal α2β4 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 inhibitors reduce ACh-currents and that imipramine regulates reversibly and non- competitively neuronal α2β4 and muscle AChRs through similar mechanisms, perhaps by interacting externally on a non-conducting state of the AChR and by blocking the open receptor-channel complex close to the vestibule of the channel. These studies may be important for understanding the regulation of AChRs as well as for understanding antidepressant- and side-effects of monoamine-uptake inhibitors.
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Acknowledgements
We are grateful to Dr Ricardo Miledi for initiating these experiments and for subsequent invaluable help during this work. We are also grateful to Drs J Boulter and S Heinemann (The Salk Institute) for providing the AChR clones, and MSc Marina Herrera González for preparing cRNAs. This work was supported by Grants from Consejo Nacional de Ciencia y Tecnología, México 3717P-N9608 and G25775N (to JGC) and a DGEP UNAM scholarship to HELV.
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López-Valdés, H., García-Colunga, J. Antagonism of nicotinic acetylcholine receptors by inhibitors of monoamine uptake. Mol Psychiatry 6, 511–519 (2001). https://doi.org/10.1038/sj.mp.4000885
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DOI: https://doi.org/10.1038/sj.mp.4000885
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