Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Research Article
  • Published:

Antagonism of nicotinic acetylcholine receptors by inhibitors of monoamine uptake

Molecular Psychiatry volume 6, pages 511–519 (2001)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Clementi F, Fornasari D, Gotti C . Neuronal nicotinic receptors, important new players in brain function Eur J Pharmacol 2000 393: 3–10

    Article  CAS  Google Scholar 

  2. Karlin A, Akabas MH . Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins Neuron 1995 15: 1231–1244

    Article  CAS  Google Scholar 

  3. McGhee DS . Molecular diversity of neural acetylcholine receptor Ann NY Acad Sci 1999 868: 565–577

    Article  Google Scholar 

  4. Lukas RJ, Bencherif M . Heterogeneity and regulation of nicotinic acetylcholine receptors Int Rev Neurobiol 1992 34: 25–131

    Article  CAS  Google Scholar 

  5. Arias HR . Binding sites for exogenous and endogenous non-competitive inhibitors of the nicotinic acetylcholine receptor Biochim Biophys Acta 1998 1376: 173–220

    Article  CAS  Google Scholar 

  6. Barnes NM, Sharp T . A review of central 5-HT receptors and their function Neuropharmacology 1999 38: 1083–1152

    Article  CAS  Google Scholar 

  7. Grassi F, Polenzani L, Mileo AM, Caratsch CG, Eusebi F, Miledi R . Blockage of nicotinic acetylcholine receptors by 5-hydroxytryptamine J Neurosci Res 1993 34: 562–570

    Article  CAS  Google Scholar 

  8. García-Colunga J, Miledi R . Serotonergic agents block neuronal nicotinic acetylcholine receptors expressed in oocytes FASEB J 1994 8: 622 (abstract)

    Article  Google Scholar 

  9. García-Colunga J, Miledi R . Effects of serotonergic agents on neuronal nicotinic acetylcholine receptors Proc Natl Acad Sci USA 1995 92: 2919–2923

    Article  Google Scholar 

  10. García-Colunga J, Miledi R . Serotonergic modulation of muscle acetylcholine receptors of different subunit composition Proc Natl Acad Sci USA 1996 93: 3990–3994

    Article  Google Scholar 

  11. García-Colunga J, Miledi R . Blockage of mouse muscle nicotinic receptors by serotonergic compounds Exp Physiol 1999 84: 847–864

    Article  Google Scholar 

  12. Palma E, Mileo AM, Eusebi F, Miledi R . Threonine-for-leucine mutation within domain M2 of the neuronal α7 nicotinic receptor converts 5-hydroxytryptamine from antagonist to agonist Proc Natl Acad Sci USA 1996 93: 11231–11235

    Article  CAS  Google Scholar 

  13. García-Colunga J, Awad JN, Miledi R . Blockage of muscle and neuronal nicotinic acetylcholine receptors by fluoxetine (Prozac) Proc Natl Acad Sci USA 1997 94: 2041–2044

    Article  Google Scholar 

  14. García-Colunga J, Awad JN, Miledi R . Blockage of muscle acetylcholine receptors by the serotonin 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) Biomed Res 1997 18: 307–311

    Article  Google Scholar 

  15. Palma E, Maggi L, Eusebi F, Miledi R . Neuronal nicotinic threonine-for-leucine 247 α7 mutant receptors show different gating kinetics when activated by acetylcholine or by the noncompetitive agonist 5-hydroxytriptamine Proc Natl Acad Sci USA 1997 94: 9915–9919

    Article  CAS  Google Scholar 

  16. Fryer JD, Lukas RJ . Antidepressants noncompetitively inhibit nicotinic acetylcholine receptor function J Neurochem 1999 72: 1117–1124

    Article  CAS  Google Scholar 

  17. Hennings ECP, Kiss JP, De Oliveira K, Toth PT, Vizi ES . Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices J Neurochem 1999 73: 1043–1050

    Article  CAS  Google Scholar 

  18. Cusack B, Nelson A, Richelson E . Binding of antidepressants to human brain receptors: focus on newer generation compounds Psychopharmacology 1994 114: 559–565

    Article  CAS  Google Scholar 

  19. Owens MJ, Morgan WN, Plott SJ, Nemeroff CB . Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites J Pharmacol Exp Ther 1997 283: 1305–1322

    PubMed  CAS  Google Scholar 

  20. Wong DT, Bymaster FP, Engleman EA . Prozac (Fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication Life Sci 1995 57: 411–441

    Article  CAS  Google Scholar 

  21. Ni YG, Miledi R . Blockage of 5HT2C serotonin receptors by fluoxetine (Prozac) Proc Natl Acad Sci USA 1997 94: 2036–2040

    Article  CAS  Google Scholar 

  22. Maggi L, Palma E, Miledi R, Eusebi F . Effects of fluoxetine on wild and mutant neuronal α7 nicotinic receptors Mol Psychiatry 1998 3: 350–355

    Article  CAS  Google Scholar 

  23. Richelson E . Synaptic effects of antidepressants J Clin Psychopharmacol 1996 16 suppl 2: 1S–7S

    Article  Google Scholar 

  24. Aronstam RS . Interactions of tricyclic antidepressants with a synaptic ion channel Life Sci 1981 28: 59–64

    Article  CAS  Google Scholar 

  25. Eldefrawi ME, Warnick JE, Schofield GG, Albuquerque EX, Eldefrawi AT . Interaction of imipramine with the ionic channel of the acetylcholine receptor of motor endplate and electric organ Biochem Pharmacol 1981 30: 1391–1394

    Article  CAS  Google Scholar 

  26. Rana B, McMorn SO, Reeve HL, Wyatt CN, Vaughan PFT, Peers C . Inhibition of neuronal nicotinic acetylcholine receptors by imipramine and desimipramine Eur J Pharmacol 1993 250: 247–251

    Article  CAS  Google Scholar 

  27. Izaguirre V, Fernández-Fernández JM, Ceña V, González-García C . Tricyclic antidepressants block cholinergic nicotinic receptors and ATP secretion in bovine chromaffin cells FEBS Lett 1997 418: 39–42

    Article  CAS  Google Scholar 

  28. Miledi R, Woodward RM . Effects of defolliculation on membrane current responses of Xenopus oocytes J Physiol (Lond) 1989 416: 601–621

    Article  CAS  Google Scholar 

  29. Miledi R . A calcium-dependent transient outward current in Xenopus laevis oocytes Proc R Soc Lond 1982 B 215: 491–497

    PubMed  Google Scholar 

  30. Woodhull AM . Ionic blockage of sodium channels in nerve J Gen Physiol 1973 61: 687–708

    Article  CAS  Google Scholar 

  31. Feltz A, Trautmann A . Interaction between nerve-released acetylcholine and bath applied agonists at frog end-plate J Physiol (Lond) 1980 299: 533–552

    Article  CAS  Google Scholar 

  32. Garattini S, Barbui C, Saraceno B . Antidepressant agents: from tricyclics to serotonin uptake inhibitors Psychol Med 1998 28: 1169–1178

    Article  CAS  Google Scholar 

  33. Zwart R, Vijverberg HPM . Potentiation and inhibition of neural nicotinic receptors by atropine: competitive and noncompetitive effects Mol Pharmacol 1997 52: 886–895

    Article  CAS  Google Scholar 

  34. Le Novère N, Changeux JP . Molecular evolution of the nicotinic acetylcholine receptor: an example of multigene family in excitable cells J Mol Evol 1995 40: 155–172

    Article  Google Scholar 

  35. Eterovic VA, Li L, Ferchmin PA, Lee YH, Hann RM, Rodriguez AD et al. The ion channel of muscle and electric organ acetylcholine receptors: differing affinities for noncompetitive inhibitors Cell Mol Neurobiol 1993 13: 111–121

    Article  CAS  Google Scholar 

  36. Colomo F, Rahamimoff R, Stefani E . An action of 5-hydroxytryptamine on the frog motor end-plate Eur J Pharmacol 1968 3: 272–274

    Article  CAS  Google Scholar 

  37. Akasu T, Koketsu K . 5-Hydroxytryptamine decreases the sensitivity of nicotinic acetylcholine receptor in bull-frog sympathetic ganglion cells J Physiol (Lond) 1986 380: 93–109

    Article  CAS  Google Scholar 

  38. Hahn SJ, Choi JS, Rhie DJ, Oh CS, Jo YH, Kim MS . Inhibition by fluoxetine of voltage-activated ion channels in rat PC12 cells Eur J Pharmacol 1999 367: 113–118

    Article  CAS  Google Scholar 

  39. Hollister LE . Plasma concentration of tryciclic antidepressants in clinical practice J Clin Psychiatry 1982 43: 66–69

    PubMed  CAS  Google Scholar 

  40. Besret L, Debruyne D, Rioux P, Bonvalot T, Moulin M, Zarifian E et al. A comprehensive investigation of plasma and brain regional pharmacokinetics of imipramine and its metabolites during and after chronic administration in the rat J Pharmacol Sci 1996 85: 291–295

    CAS  Google Scholar 

  41. Lukas RJL . Cell lines as models for studies of nicotinic acetylcholine receptors. In: Arneric SP, Brioni JD (eds) Neuronal Nicotinic Receptors Wiley-Liss: New York 1999 81–97

    Google Scholar 

  42. Paterson D, Nordberg A . Neuronal nicotinic receptors in the human brain Prog Neurobiol 2000 61: 75–111

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Centro de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Apartado Postal 1–1141, Juriquilla, 76001, Querétaro, México

    H E López-Valdés & J García-Colunga

Authors
  1. H E López-Valdés
    View author publications

    Search author on:PubMed Google Scholar

  2. J García-Colunga
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to J García-Colunga.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/sj.mp.4000885

Keywords

This article is cited by

Search

Advanced search

Quick links