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Bupropion, a Food and Drug Administration-approved antidepressant and smoking cessation aid, blocks dopamine and norepinephrine reuptake transporters and noncompetitively inhibits nicotinic acetylcholine and serotonin (5-HT) type 3A receptors (5-HT 3A Rs). 5-HT 3 receptors are pentameric ligand-gated ion channels that regulate synaptic activity in the central and peripheral nervous system, presynaptically and postsynaptically. In the present study, we examined and compared the effect of bupropion and its active metabolite hydroxybupropion on mouse homomeric 5-HT 3A and heteromeric 5-HT 3AB receptors expressed in Xenopus laevis oocytes using two-electrode voltage clamp experiments. Coapplication of bupropion or hydroxybupropion with 5-HT dose dependently inhibited 5-HT-induced currents in heteromeric 5-HT type 3AB receptors (5-HT 3AB Rs) (IC 50 = 840 and 526 μM, respectively). The corresponding IC 50 s for bupropion and hydroxybupropion for homomeric 5-HT 3A Rs were 10- and 5-fold lower, respectively (87 and 113 μM). The inhibition of 5-HT 3A Rs and 5-HT 3AB Rs was non-use dependent and voltage independent, suggesting bupropion is not an open channel blocker. The inhibition by bupropion was reversible and time-dependent. Of note, preincubation with a low concentration of bupropion that mimics therapeutic drug conditions inhibits 5-HT-induced currents in 5-HT 3A and 5-HT 3AB receptors considerably. In summary, we demonstrate that bupropion inhibits heteromeric 5-HT 3AB Rs as well as homomeric 5-HT 3A Rs. This inhibition occurs at clinically relevant concentrations and may contribute to bupropion's clinical effects. SIGNIFICANCE STATEMENT: Clinical studies indicate that antagonizing serotonin (5-HT) type 3AB (5-HT 3AB ) receptors in brain areas involved in mood regulation is successful in treating mood and anxiety disorders. Previously, bupropion was shown to be an antagonist at homopentameric 5-HT type 3A receptors. The present work provides novel insights into the pharmacological effects that bupropion exerts on heteromeric 5-HT 3AB receptors, in particular when constantly present at low, clinically attainable concentrations. The results advance the knowledge on the clinical effects of bupropion as an antidepressant.

Bupropion Inhibits Serotonin Type 3AB Heteromeric Channels at Clinically Relevant Concentrations