Psychopharmacology (2006) 184: 426–434 DOI 10.1007/s00213-005-0163-8 ORIGINAL INVESTIGATION N. M. Neugebauer . Z. Zhang . P. A. Crooks . L. P. Dwoskin . M. T. Bardo Effect of a novel nicotinic receptor antagonist, N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide, on nicotine self-administration and hyperactivity in rats Received: 21 January 2005 / Accepted: 4 August 2005 / Published online: 12 October 2005 # Springer-Verlag 2005 Abstract Rationale and objective: Recent work has shown that the novel compound N,N′-dodecane-1,12- diyl-bis-3-picolinium dibromide (bPiDDB) may selec- tively block nicotinic acetylcholine receptors involved in regulating dopamine release. The current experiments examined the acute effect of bPiDDB on nicotine self- administration, sucrose-maintained responding, and nico- tine-induced changes in acute and sensitized locomotor activity. Methods: Rats were first trained to respond for either nicotine (i.v.) or sucrose pellets using a standard two-lever operant conditioning procedure using a fixed ratio 5 schedule of reinforcement and were then pretreated with bPiDDB (0, 0.3, 1, or 3 mg kg -1 ) 15 min prior to the session. In separate experiments, rats were assessed for nicotine-induced changes in locomotor activity following pretreatment with bPiDDB (1 or 3 mg kg -1 ) or mecamyl- amine (1 mg kg -1 ); pretreatments were assessed with both acute and repeated nicotine (0.4 mg kg -1 ) treatment. Results: Results showed that bPiDDB dose-dependently decreased nicotine self-administration, but not sucrose- maintained responding. In the locomotor experiments, bPiDDB attenuated the hyperactivity produced by acute and repeated nicotine; however, this effect was not robust compared to mecamylamine. In contrast to mecamyl- amine, bPiDDB did not block the initial hypoactivity produced by acute nicotine. Conclusion: Since bPiDDB decreased nicotine self-administration specifically, this novel nicotinic receptor antagonist may constitute a lead for the development of a clinically useful treatment for tobacco dependence. Keywords bPiDDB . Nicotine . Mecamylamine . Self-administration . Locomotor activity . Nicotinic receptor antagonist . Tobacco dependence Introduction While the reinforcing and dependence liability of nicotine involves a host of neurotransmitters, the mesolimbic dopamine (DA) system is thought to be critically involved in these processes (Benwell and Balfour 1992; Corrigall et al. 1992). Given the role of mesolimbic DA in nicotine addiction, the specific nicotinic acetylcholine receptors (nAChRs) modulating DA release may offer a viable mo- lecular target for the development of novel medications to treat tobacco dependence. Mecamylamine is a nonselec- tive, noncompetitive antagonist at all nicotinic receptors, whereas dihydro-β-erythroidine (DHβE) is a preferential antagonist for high affinity nicotinic receptors, including the α4β2* nAChR, and methyllycaconitine (MLA) is relatively selective for the low affinity α7* nAChR. Im- portantly, mecamylamine and DHβE decrease nicotine self-administration (Grottick et al. 2000), indicating that high affinity nAChRs are critically involved in the re- inforcing effect of nicotine. This conclusion is corrobora- ted by evidence showing that mice lacking the β2 subunit do not self-administer nicotine (Epping-Jordan et al. 1999; Picciotto et al. 1998). In addition, since MLA also dimin- ishes nicotine self-administration and the nicotine-induced decrease in brain stimulation reward threshold (Markou and Paterson 2001; Panagis et al. 2000), low affinity α7* nAChRs may also be involved in nicotine reward. Although there is no subtype-selective nAChR antago- nist that targets the specific nAChR subtype(s) mediating nicotine-evoked DA release currently commercially avail- able, a selective nAChR antagonist might be a potential N. M. Neugebauer . M. T. Bardo (*) Department of Psychology, University of Kentucky, Lexington, KY 40506, USA e-mail: mbardo@uky.edu Tel.: +1-859-2576456 Fax: +1-859-3231979 Z. Zhang . P. A. Crooks . L. P. Dwoskin College of Pharmacy, University of Kentucky, Lexington, KY USA