Abstract

Bupropion is an atypical antidepressant that also has usefulness as a smoking-cessation aid. Because hydroxybupropion, a major metabolite of bupropion, is believed to contribute to its antidepressant activity, this metabolite may also contribute to the smoking-cessation properties of bupropion. This study investigated the effects of hydrobupropion enantiomers on monoamine transporters and nicotinic acetylcholine receptor (nAChR) subtypes. Racemic bupropion and hydroxybupropion inhibit [³H]norepinephrine (NE) uptake with similar potency (IC₅₀ values of 1.9 and 1.7 μM, respectively), but most of the latter activity resides in the (2S,3S)-hydroxy isomer (IC₅₀ = 520 nM) rather than (2S,3R)-hydroxybupropion (IC₅₀ > 10,000 nM). Similar results were found with [³H]dopamine (DA) uptake. The effects of bupropion and enantiomers of hydroxybupropion on human nAChR subtypes indicate that the (2S,3S) isomer is more potent than the (2S,3R) isomer or racemic bupropion as an antagonist of α₄β₂ (functional IC₅₀ = 3.3 μM). In addition, (2S,3S)-hyroxybupropion and bupropion were considerably more potent than (2R, –3R)-hydroxybupropion in a mouse depression model (forced swimming test) and in antagonism of acute nicotine effects in mice. Together, our results suggest that clinical and behavioral effects of bupropion arise from actions at nAChR as well as DA and NE transporters. Furthermore, our data suggest that the (2S,3S)-hydroxybupropion isomer may be a better drug candidate for smoking cessation than bupropion because of its higher potency at the relevant targets.