Genes coding for nicotinic acetylcholine receptor (nAChRs) and genes within the dopamine reward system are plausible candidates for pharmacogenetic investigations of bupropion. Nicotine activates α4β2 nAChRs to stimulate dopamine release, which plays a key role in signaling the reward system (7). Bupropion inhibits dopamine re-uptake, resulting in higher levels of dopamine, which is believed to be responsible for alleviating the cognitive and affective symptoms of nicotine withdrawal, as demonstrated in preclinical (8,9) and human studies (8,10,11). Consistent with these data, several studies have identified associations of single nucleotide polymorphisms (SNPs) in dopaminergic and nAChR subunit genes with nicotine dependence (12–16) and with smoking cessation during the treatment with bupropion (17–22). While the α4β2 nAChRs account for the majority of high affinity binding related to dopamine release, nAChRs on dopaminergic neurons may also contain α5, α6 and β3 subunits, which may contribute to receptor targeting, localization and receptor permeability (23).
