Bupropion inhibits nicotine-evoked [³H]overflow from rat striatal slices preloaded with [³H]dopamine and from rat hippocampal slices preloaded with [³H]norepinephrine

Bupropion, an efficacious antidepressant and smoking cessation agent, inhibits dopamine and norepinephrine transporters (DAT and NET, respectively). Recently, bupropion has been reported to noncompetitively inhibit α3β2, α3β4, and α4β2 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes or established cell lines. The present study evaluated bupropion-induced inhibition of native α3β2* and α3β4* nAChRs using functional neurotransmitter release assays, nicotine-evoked [³H]overflow from superfused rat striatal slices preloaded with [³H]dopamine ([³H]DA), and nicotine-evoked [³H]overflow from hippocampal slices preloaded with [³H]norepinephrine ([³H]NE). The mechanism of inhibition was evaluated using Schild analysis. To eliminate the interaction of bupropion with DAT or NET, nomifensine or desipramine, respectively, was included in the superfusion buffer. A high bupropion concentration (100 μM) elicited intrinsic activity in the [³H]DA release assay. However, none of the concentrations (1 nM-100 μM) examined evoked [³H]NE overflow and, thus, were without intrinsic activity in this assay. Moreover, bupropion inhibited both nicotine-evoked [³H]DA overflow (IC₅₀ = 1.27 μM) and nicotine-evoked [³H]NE overflow (IC₅₀ = 323 nM) at bupropion concentrations well below those eliciting intrinsic activity. Results from Schild analyses suggest that bupropion competitively inhibits nicotine-evoked [³H]DA overflow, whereas evidence for receptor reserve was obtained upon assessment of bupropion inhibition of nicotine-evoked [³H]NE overflow. Thus, bupropion acts as an antagonist at α3β2* and α3β4* nAChRs in rat striatum and hippocampus, respectively, across the same concentration range that inhibits DAT and NET function. The combination of nAChR and transporter inhibition produced by bupropion may contribute to its clinical efficacy as a smoking cessation agent.