Atypical antipsychotic drug olanzapine inhibits 5-HT3 receptor-mediated currents by allosteric and non-competitive mechanisms.

Olanzapine, an atypical antipsychotic, is widely used in the treatment of schizophrenia and bipolar disorder due to its modulation of dopamine and serotonin receptor systems. While its primary action involves antagonism of dopamine D2 and serotonin 5-HT (5-hydroxytryptamine)₂A receptors, recent evidence suggests that olanzapine also inhibits 5-HT₃ receptors, which are ligand-gated ion channels involved in synaptic transmission in central and peripheral nervous systems. The present study aimed to investigate the action of olanzapine on 5-HT₃ receptor-mediated currents using whole-cell voltage-clamp recordings in NCB-20 neuroblastoma cells. Results of this study indicated that olanzapine could act as a non-competitive antagonist of the 5-HT₃ receptor, exhibiting concentration-dependent inhibition of ion currents. Moreover, olanzapine facilitated both deactivation and desensitization kinetics, accelerating decay of 5-HT₃ receptor-mediated currents. Recovery from desensitization was significantly delayed by olanzapine, whereas recovery from deactivation was largely unaffected by it. Current-voltage relationship analysis revealed that olanzapine reduced the amplitude of 5-HT₃ receptor-mediated currents across all holding potentials without altering reversal potential, suggesting a voltage-independent inhibition. Furthermore, olanzapine exhibited use-dependent inhibition, with a greater reduction in current observed during more frequent 5-HT application. These findings provide novel insights into a non-competitive and allosteric inhibition of 5-HT₃ receptors by olanzapine, contributing to a deeper understanding of its pharmacological profile in neuropsychiatric and gastrointestinal conditions where serotonergic neurotransmission is implicated.