The
serotonin type 3 (5-HT(3)) receptor is the only
ligand-gated ion channel receptor for
serotonin (5-HT). 5-HT(3) 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-HT(2)) receptors. Except for
clozapine, a direct pharmacological interaction of
neuroleptics with 5-HT(3) 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-HT(3) 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 Ca(2+) influx, measured as a change in intracellular Ca(2+) concentrations ([Ca(2+)](i)). All
neuroleptic drugs, but not
risperidone, antagonized Na(+)- and Ca(2+)-inward currents evoked by
5-HT (10 microM for 2 s and 1 microM, 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 IC(50) values, indicating that a change in membrane anisotropy might contribute to their antagonistic effect at the 5-HT(3) receptor. Only structure analogues of
flupentixol and
fluphenazine with a lipophilic side chain were potent antagonists against 5-HT-evoked Na(+) and Ca(2+) currents. Since 5-HT(3) receptors modulate mesolimbic and mesocortical dopaminergic activity, the functional antagonism of
neuroleptics at 5-HT(3) receptors may contribute to their
antipsychotic efficacy and may constitute a not yet recognized pharmacological principle of these drugs.