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

G. Rammes, B. Eisensamer, U. Ferrari, M. Shapa, G. Gimpl, K. Gilling, C. Parsons, K. Riering, G. Hapfelmeier, B. Bondy, W. Zieglgänsberger, F. Holsboer, R. Rupprecht

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55 Scopus citations


The serotonin type 3 (5-HT3) receptor is the only ligand-gated on 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-HT 3 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 2s 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 nouroleptics at 5-HT3 receptors may contribute to their antipsychotic efficacy and may constitute a not yet recognized pharmacological principle of these drugs.

Original languageEnglish
Pages (from-to)846-858
Number of pages13
JournalMolecular Psychiatry
Issue number9
StatePublished - Sep 2004
Externally publishedYes


  • 5-HT receptor
  • Antipsychotics
  • Ligand-gated ion channels
  • Neuroleptics
  • Patch clamp
  • Serotonin


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