Abstract
The 5-hydroxytryptamine type(3) (5-HT(3)) receptor, a ligand-gated ion channel, plays a critical role in synaptic transmission. It has been implicated in various neuropsychiatric disorders. This study aimed to elucidate the mechanism by which quetiapine, an atypical antipsychotic, could inhibit 5-HT(3) receptor-mediated currents in NCB20 neuroblastoma cells. Whole-cell patch-clamp recordings were used to study effects of quetiapine on receptor ion channel kinetics and its competitive antagonism. Co-application of quetiapine shifted 5-HT concentration-response curve rightward, significantly increasing the EC50 without altering the maximal response (E(max)), suggesting a competitive inhibition. Quetiapine's IC(50) varied with 5-HT concentration and treatment condition. The IC(50) value of quetiapine was 0.58 μM with 3 μM 5-HT and 25.23 μM with 10 μM 5-HT, indicating an inverse relationship between quetiapine efficacy and agonist concentration. Pretreatment of quetiapine significantly enhanced its inhibitory potency, reducing its IC(50) from 25.23 μM to 0.20 μM. Interaction kinetics experiments revealed an IC(50) of 5.17 μM for an open state of the 5-HT(3) receptor, suggesting weaker affinity during receptor activation. Quetiapine also accelerated receptor deactivation and desensitization, suggesting that it could stabilize the receptor in non-conducting states. Additionally, quetiapine significantly prolonged recovery from desensitization without affecting recovery from deactivation, demonstrating its selective impact on receptor kinetics. Inhibition of the 5-HT(3) receptor by quetiapine was voltage-independent, and quetiapine exhibited no use-dependency, further supporting its role as a competitive antagonist. These findings provide insights into inhibitory mechanism of quetiapine on 5-HT(3) receptor and suggest its potential therapeutic implications for modulating serotonergic pathways in neuropsychiatric disorders.