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Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

Molecular Psychiatry volume 9, pages 846–858 (2004)Cite this article

Abstract

The serotonin type 3 (5-HT3) receptor is the only ligand-gated ion channel receptor for serotonin (5-HT). 5-HT3 receptors play an important role in modulating the inhibitory action of dopamine in mesocorticolimbic brain regions. Neuroleptic drugs are commonly thought to exert their psychopharmacological action mainly through dopamine and serotonin type 2 (5-HT2) receptors. Except for clozapine, a direct pharmacological interaction of neuroleptics with 5-HT3 receptors has not yet been described. Using the concentration-clamp technique, we investigated the effects of flupentixol, various phenothiazines, haloperidol, clozapine and risperidone on Na+-inward currents through 5-HT3 receptors stably expressed in human embryonic kidney 293 cells, and through endogenous 5-HT3 receptors of murine N1E-115 neuroblastoma cells. In addition, we studied their effects on Ca2+ influx, measured as a change in intracellular Ca2+ concentrations ([Ca2+]i). All neuroleptic drugs, but not risperidone, antagonized Na+- and Ca2+-inward currents evoked by 5-HT (10 μM for 2 s and 1 μM, respectively) in a voltage-independent manner. Only clozapine was a competitive antagonist, while all other compounds turned out to be noncompetitive. Fluphenazine and haloperidol affected membrane anisotropy at concentrations below their IC50 values, indicating that a change in membrane anisotropy might contribute to their antagonistic effect at the 5-HT3 receptor. Only structure analogues of flupentixol and fluphenazine with a lipophilic side chain were potent antagonists against 5-HT-evoked Na+ and Ca2+ currents. Since 5-HT3 receptors modulate mesolimbic and mesocortical dopaminergic activity, the functional antagonism of neuroleptics at 5-HT3 receptors may contribute to their antipsychotic efficacy and may constitute a not yet recognized pharmacological principle of these drugs.

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Acknowledgements

We thank Iris Bauer, Sonja Wirth, Christiane Rewerts, Sabrina Meyr and Sylvia de Jonge for expert technical assistance. This work was supported by a Tandem Project of the Max-Planck-Society and the Deutsche Forschungsgemeinschaft (DFG) (Ru 426/6-1). Parts of this work are parts from the thesis of Uta Ferrari at the medical faculty, Ludwig-Maximilians-Universität, Munich, Germany.

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  1. G Rammes and B Eisensamer: Both authors contributed equally to this work

Authors and Affiliations

  1. Max-Planck-Institute of Psychiatry, Munich, Germany

    G Rammes, B Eisensamer, U Ferrari, K Riering, G Hapfelmeier, W Zieglgänsberger, F Holsboer & R Rupprecht

  2. Department of Psychiatry, Ludwig-Maximilians-Universität, Munich, Germany

    B Eisensamer, M Shapa, K Riering, B Bondy & R Rupprecht

  3. Institute of Biochemistry, Johannes-Gutenberg-Universität, Mainz, Germany

    G Gimpl

  4. Merz Pharmaceuticals, Frankfurt/Main, Germany

    K Gilling & C Parsons

  5. Department of Anaesthesiology, Technische Universität München, Munich, Germany

    G Hapfelmeier

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Correspondence to R Rupprecht.

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Rammes, G., Eisensamer, B., Ferrari, U. et al. Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner. Mol Psychiatry 9, 846–858 (2004). https://doi.org/10.1038/sj.mp.4001490

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