Complex Modulation of the GABAA α1β2γ2 Receptor Function by Bupropion

Bupropion is one of the most common drugs prescribed for treating depression and aiding smoking cessation, and is generally well tolerated with the exception of a rare dose-dependent incidence of seizures. It inhibits norepinephrine and dopamine reuptake, as well as noncompetitively antagonizes neuronal nicotinic acetylcholine receptors, which are members of the Cys-loop superfamily. While investigating its effects on other key members of this superfamily, bupropion showed complex modulation of the γ-aminobutyric acid type A (GABAA) α1β2γ2 receptor function.In the brain, GABAA α1β2γ2 receptors are one of the most abundant chloride-conducting hetero-pentameric ligand-gated ion channels. They are targets for a number of drugs including anesthetics, anticonvulsants, anxiolytics, hypnotics, and muscle relaxants.To the best of our knowledge, the interaction of bupropion with the GABAA receptor has not yet been described. Therefore, the primary goal of this study was to characterize the functional interactions of bupropion with the GABAA α1β2γ2 receptor. In oocytes, bupropion-alone (0.1 mM - 3 mM) directly activated GABAA receptor-mediated currents. The comparison of dose-response curves showed that bupropion-activation was lower in potency (EC50=1.5 mM vs. 1.3 μM) and efficacy (49.5% vs. 100%) than that for GABA, consistent with partial agonism of the GABAA receptor. Interestingly, at lower concentrations (0.001 µM - 100 μM) bupropion inhibited 0.5 μM GABA-induced currents by ∼ 8 - 20%; in contrast, at higher concentrations (1 mM - 3 mM) it potentiated GABA-induced currents by ∼ 50 - 70%. Notably, in many ways bupropion mimics the actions of some of the general anesthetics (e.g. propofol) at the GABAA receptor. This warrants exploring the bupropion binding site(s) within these receptors.