The current study evaluated a new series of N, analogs with C 6 -C 12 methylene linkers as nicotinic acetylcholine receptor (nAChR) antagonists, for nicotine-evoked [ 3 H]dopamine (DA) overflow, for blood-brain barrier choline transporter affinity, and for attenuation of discriminative stimulus and locomotor stimulant effects of nicotine. bAPi analogs exhibited little affinity for ␣4␤2* (* indicates putative nAChR subtype assignment) and ␣7* high-affinity ligand binding sites and exhibited no inhibition of DA transporter function. With the exception of C 6 , all analogs inhibited nicotine-evoked [ 3 H]DA overflow (IC 50 ϭ 2 nM-6 M; I max ϭ 54 -64%), with N, C 12 ) being most potent. bPiDDB did not inhibit electrically evoked [ 3 H]DA overflow, suggesting specific nAChR inhibitory effects and a lack of toxicity to DA neurons. Schild analysis suggested that bPiDDB interacts in an orthosteric manner at nAChRs mediating nicotine-evoked [ 3 H]DA overflow.To determine whether bPiDDB interacts with ␣-conotoxin MIIsensitive ␣6␤2-containing nAChRs, slices were exposed concomitantly to maximally effective concentrations of bPiDDB (10 nM) and ␣-conotoxin MII (1 nM). Inhibition of nicotine-evoked [ 3 H]DA overflow was not different with the combination compared with either antagonist alone, suggesting that bPiDDB interacts with ␣6␤2-containing nAChRs. C 7 , C 8 , C 10 , and C 12 analogs exhibited high affinity for the blood-brain barrier choline transporter in vivo, suggesting brain bioavailability. Although none of the analogs altered the discriminative stimulus effect of nicotine, C 8 , C 9 , C 10 , and C 12 analogs decreased nicotine-induced hyperactivity in nicotine-sensitized rats, without reducing spontaneous activity. Further development of nAChR antagonists that inhibit nicotine-evoked DA release and penetrate brain to antagonize DA-mediated locomotor stimulant effects of nicotine as novel treatments for nicotine addiction is warranted.Nicotine, the principal tobacco alkaloid, is an agonist at neuronal nicotinic acetylcholine receptor (nAChR) subtypes modulating dopamine (DA) release. Habitual tobacco smoking is maintained via rapid nicotine delivery to brain (Le Foll and Goldberg, 2006) and results from the intrinsic rewarding properties of nicotine, believed to be due to increased DA release. Classical nAChR antagonists mecamylamine and dihydro-␤-erythroidine (DH␤E) inhibit nicotine-evoked DA release and decrease the locomotor stimulant and reinforcing effects of nicotine in rats Watkins et al., 1999;Rahman et al., 2004), suggesting a role for nAChRmediated DA release in these abuse-related behavioral efThis research was supported by National Institutes of Health Grants K02 DA00399, T32 DA007304, and U19 DA017548.Potential royalty payments to L.P.D., P.A.C., and J.T.A. may occur consistent with the University of Kentucky policy.Article, publication date, and citation information can be found at

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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 ␣3␤2, ␣3␤4, and ␣4␤2 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes or established cell lines. The present study evaluated bupropion-induced inhibition of native ‫ء2␤3␣‬ and ‫ء4␤3␣‬ nAChRs using functional neurotransmitter release assays, nicotine-evoked 3 H]NE overflow. Thus, bupropion acts as an antagonist at ‫ء2␤3␣‬ and ‫ء4␤3␣‬ 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.

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