1. ¹Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA
2. ²Department of Psychiatry, Cedars-Sinai Medical Center, Los Angeles, CA, USA
3. ³Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

Correspondence: Dr X Liu, Department of Psychology, University of Pittsburgh, 3131 Sennott Square, 120 S Bouquet Street, Pittsburgh, PA 15260, USA. Tel: +1 412 624 7345; Fax: +1 412 624 8558; E-mail: xiuliu@pitt.edu

Received 11 December 2005; Revised 26 April 2006; Accepted 9 May 2006; Published online 21 June 2006.

Abstract

Mecamylamine, a noncompetitive nicotinic cholinergic antagonist, inhibits nicotine self-administration in animals and may attenuate tobacco smoking in humans trying to quit. Our preliminary data suggested that this agent, at a dose of 2 mg/kg (subcutaneous (s.c.)), also attenuates cue-induced relapse to nicotine-seeking behavior in rats. This study determined whether mecamylamine-induced attenuation can be obtained at doses lower than the high 2 mg/kg dose used in the first study, and whether it is specific to nicotine-associated cues. Male Sprague–Dawley rats were trained to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed-ratio 5 schedule. Each infusion was accompanied by a visual cue (1 s onset of a lever light followed by offset of a house light for 20 s during which time no infusions could be obtained). After the nicotine-maintained responding was extinguished by withholding the delivery of nicotine (saline substitution) and its associated cue, reinstatement tests were conducted. Response-contingent re-presentation of the cue without further availability of nicotine significantly reinstated extinguished responding at the previously nicotine-reinforced lever. Pretreatment with mecamylamine (0.5, 1, and 2 mg/kg, s.c.) dose-dependently attenuated the cue-induced reinstatement of lever responding. Mecamylamine did not change food-taking and -seeking responses, whereas the highest dose (2 mg/kg) decreased nicotine self-administration behavior. The results confirm previous findings that stimuli conditioned to nicotine self-administration effectively elicit reinstatement of nicotine-seeking behavior after extinction and demonstrate that mecamylamine, besides suppressing self-administration of nicotine, effectively attenuates cue-induced nicotine-seeking behavior. These findings suggest that the response-reinstatement procedures used in this study may be useful for studying neurobiological mechanisms of nicotine-seeking behavior and that mecamylamine-like drugs may be potential candidates for pharmacological treatment and prevention of relapse to tobacco smoking in abstinent smokers.