Effects of the selective dopamine D 3 receptor antagonist SB-277011A on the reinforcing effects of nicotine as measured by a progressive-ratio schedule in rats Jason T. Ross a , William A. Corrigall a,b , Christian A. Heidbreder c , Mark G. LeSage a, ⁎ a Minneapolis Medical Research Foundation 914 South 8th Street Minneapolis, MN 55404, USA b Department of Psychiatry University of Minnesota, MN, 55414, USA c Center of Excellence for Drug Discovery in Psychiatry GlaxoSmithKline Pharmaceuticals Verona, Italy Received 26 October 2006; received in revised form 27 December 2006; accepted 9 January 2007 Available online 19 January 2007 Abstract The dopamine D 3 receptor is primarily localized within the mesocorticolimbic system, and may therefore have potential as a pharmacotherapeutic target for the treatment of drug dependence. Studies have shown that the selective dopamine D 3 receptor antagonist SB- 277011A reduces a variety of dependence-related behavioral effects of cocaine, alcohol and heroin. A previous study examining SB-277011A on nicotine self-administration using relatively low doses of the antagonist and a low response requirement for nicotine found no effect on drug- taking behavior per se, whereas reinstatement of nicotine-seeking was reduced. The purpose of the present study was to further examine the effects of higher doses of SB-277011A on nicotine self-administration in rats under a progressive-ratio (PR) schedule, which imposes relatively high response requirements for nicotine. Rats were trained to respond under a PR schedule of either nicotine or food reinforcement. Once responding was stable, SB-277011A (3–56 mg/kg) or vehicle was administered i.p. 1 h prior to the operant session. The highest dose tested significantly decreased the mean number of reinforcers and mean response rates in the nicotine self-administration group, but had no effect on either the mean number of reinforcers or response rate in the food group. In a separate set of experiments, the effects of SB-277011A on locomotor activity were measured. At the dose that significantly decreased nicotine self-administration, total distance traveled was also significantly decreased, suggesting that the effect on operant responding at the high dose of SB-277011A is at a threshold for motor effects and may not be directly mediated by an action at dopamine D 3 receptors. © 2007 Elsevier B.V. All rights reserved. Keywords: Nicotine; Self-administration; Dopamine D 3 receptor; Antagonist; SB-277011A 1. Introduction Nicotine, the primary psychoactive drug in tobacco smoke, has been shown to activate the mesolimbic dopamine system (Corrigall et al., 1992, 1994; Balfour, 2004). Activation of this system is integral in the reinforcing properties of several drugs of abuse (for review, see Wise, 2004). Because the neuroana- tomical distribution of the D 3 receptor is primarily localized within the mesolimbic dopamine system, this receptor has been suggested as a primary pharmacotherapeutic target for drug addiction (Sokoloff et al., 1990; Caine and Koob, 1993; Caine et al., 1997). Investigation of the role of the dopamine D 3 receptor in drug addiction has been hampered by a lack of selective compounds. However, trans- N-[4-[2-(6-cyano- 1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinoli- necarboxamide (SB-277011A) has recently been developed as a competitive D 3 receptor antagonist with 80- to 100-fold selectivity over other dopamine receptors and high affinity for both human (pK i 7.95) and rat (pK i 7.97) cloned dopamine D 3 receptors (Reavill et al., 2000; Stemp et al., 2000). Thus, SB- 277011A and other more recent selective antagonists have served as useful tools to examine the role of D 3 receptors in the dependence-related effects of drugs of abuse (Heidbreder et al., 2005; Joyce and Millan, 2005; Newman et al., 2005). The effects of SB-277011A in animal models of drug abuse are supportive of the use of selective dopamine D 3 antagonists as potential pharmacotherapeutic agents for the treatment of European Journal of Pharmacology 559 (2007) 173 – 179 www.elsevier.com/locate/ejphar ⁎ Corresponding author. Tel.: +1 612 347 5118; fax +1 612 377 7372. E-mail address: lesage002@umn.edu (M.G. LeSage). 0014-2999/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2007.01.004