Abstract
Haloperidol is a typical antipsychotic drug effective in alleviating positive symptoms of schizophrenia by blocking dopamine receptor 2 (DR2). However, it is also known to produce neuropsychiatric effects by acting on various targets other than DR. In this study, we investigated effect of haloperidol on function of 5-hydroxytryptamine (5-HT)(3) receptor, a ligand-gated ion channel belonging to the serotonin receptor family using the whole-cell voltage clamp technique and NCB20 neuroblastoma cells. When co-applied with 5-HT, haloperidol inhibited 5-HT(3) receptormediated currents in a concentration-dependent manner. A reduction in maximal effect (E(max)) and an increase in EC(50) observed during co-application indicated that haloperidol could act as a non-competitive antagonist of 5-HT(3) receptors. Haloperidol inhibited the activation of 5-HT(3) receptor, while also accelerating their deactivation and desensitization. The inhibitory effect of haloperidol showed no significant difference between pre- and co-application. Haloperidol did not alter the reversal potential of 5-HT(3) receptor currents. Furthermore, haloperidol did not affect recovery from deactivation or desensitization of 5-HT(3) receptors. It did not show a use-dependent inhibition either. These findings suggest that haloperidol can exert its inhibitory effect on 5-HT(3) receptors by allosterically preventing opening of ion channels. This mechanistic insight enhances our understanding of relationships between 5-HT(3) receptors and pharmacological actions of antipsychotics.