[show abstract][hide abstract] 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.
[show abstract][hide abstract] ABSTRACT: Smoking-related environmental stimuli have been implicated as an important factor in triggering relapse in abstinent tobacco smokers, and recent evidence indicates that drug-associated stimuli can reinstate nicotine-seeking in rats. However, there is little investigation on the factors that contribute to the latter effect.
This study examined whether a nicotine-associated visual stimulus (VS) can reinstate nicotine-seeking after extinction in a response-reinstatement model of relapse, and whether the behavioral effects of the VS are sensitive to pharmacological blockade of nicotinic neurotransmission. It also determined whether active lever reassignment after food training influences nicotine self-administration and the VS-induced reinstatement.
Male Sprague-Dawley rats were trained to self-administer nicotine (0.03 mg/kg/infusion, IV) and associate a VS with each nicotine infusion in 30 daily 1-h sessions. Half of the animals received nicotine infusions for responding at the same lever that previously delivered food; for the other half, infusions resulted from pressing the previously inactive lever during food training. Then, the nicotine-maintained response was extinguished by saline substitution and withholding the VS. One day after rats reached extinction criterion, the reinstatement tests were conducted where the VS was response-contingent represented without further delivery of nicotine. In pharmacological tests, a nicotinic antagonist, mecamylamine, was subcutaneously administered 30 min before reinstatement sessions.
Presentation of the nicotine-associated VS significantly reinstated responding at the previously drug-reinforced lever and pretreatment with mecamylamine effectively attenuated the response-reinstating effect of the VS. Additionally, animals showed similar profiles of nicotine-taking and nicotine-seeking behavior regardless of reassignment of the active lever after food training.
Nicotine self-administration and the VS-induced reinstatement of nicotine-seeking do not result from a lever bias due to prior experience for food reinforcement. Significantly, these results suggest that environmental stimuli associated with nicotine self-administration can effectively elicit nicotine-seeking behavior in abstinent subjects, that this effect is blocked by nicotine antagonism, and that the present procedures may be useful for studying neurobiological mechanisms of nicotine-seeking behavior and relapse.