Mecamylamine attenuates cue-induced reinstatement of nicotine-seeking behavior in rats

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.