Bupropion inhibits serotonin type 3AB heteromeric channels at a physiologically relevant concentration

Bupropion, a FDA-approved antidepressant and smoking cessation aid, blocks dopamine and norepinephrine reuptake transporters and non-competitively inhibits nicotinic acetylcholine (nACh) and serotonin type 3A (5-HT 3 ) receptors. 5-HT 3 receptors are pentameric ligand-gated ion channels that regulate synaptic activity in the central and peripheral nervous system pre- and postsynaptically. In the present study, we examined and compared the effect of bupropion and its active metabolite hydroxybupropion on homomeric 5-HT 3A and heteromeric mouse 5-HT 3AB receptors expressed in Xenopus laevis oocytes using two-electrode voltage clamp experiments. Co-application of bupropion or hydroxybupropion with 5-HT dose-dependently inhibited 5-HT-induced currents in 5-HT 3AB Rs (IC 50 = 866 μM and 505 μM, respectively) but potentiated 5-HT-induced currents at low (30-50 μM) concentrations. The corresponding IC 50 s for bupropion and hydroxybupropion with 5-HT 3A R were 10- and 5-fold lower, respectively (87 μM and 113 μM), and no potentiation was observed. The inhibition of 5-HT 3A R and 5-HT 3AB R was non-use dependent and voltage-independent, indicating bupropion is not an open channel blocker. The inhibition by bupropion was reversible and time-dependent. Of note, pre-incubation with a low concentration of bupropion that mimics therapeutic drug conditions significantly inhibited 5-HT induced currents in 5-HT 3A and even more so 5-HT 3AB receptors. In summary, our results indicate that bupropion inhibits 5-HT 3AB R, as well as homomeric receptors, and that this inhibition takes place at clinically-relevant concentrations. Inhibition of 5-HT 3 receptors by bupropion may contribute to its desired and/or undesired clinical effects. Significance Statement 5-HT 3AB receptors are found in brain areas involved in mood regulation. Clinical studies indicate that antagonizing these receptors was successful in treating mood and anxiety disorders. Some currently clinically available antidepressants and antipsychotics act as antagonists of 5-HT 3 receptors. Previously, bupropion was shown to be an antagonist at homopentameric 5-HT 3A receptors. The present work provides novel insights into the pharmacological effects bupropion exerts on heteromeric 5-HT 3AB receptors. The results advance the knowledge on the clinical effect of bupropion as an antidepressant.