Mecamylamine attenuates cue-induced reinstatement of nicotine-seeking behavior in rats.
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.
Article: Antagonism of the nicotine-induced changes of the striatal dopamine metabolism in mice by mecamylamine and pempidine.[show abstract] [hide abstract]
ABSTRACT: The ability of nicotinic receptor blockers, mecamylamine and pempidine, to antagonize the changes in striatal dopamine (DA) metabolism induced by repeated nicotine administration was studied. The contents of DA and its metabolites 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured. Mice kept at 20-22 degrees C were given nicotine, 3 mg/kg, s.c., four times, at 30 min intervals, and sacrificed 20 min after the last dose. Hexamethonium, 10 mg/kg, i.p., was administered at 30 min before the first nicotine dose in order to prevent the peripheral effects of nicotine. Mecamylamine, 0.6 or 10 mg/kg, i.p., and pempidine, 0.6 or 20 mg/kg, i.p., were given at 60 min before sacrifice. Mecamylamine and pempidine decreased clearly the striatal 3-MT content, which suggests that the nigrostriatal dopaminergic neurons are physiologically controlled by a stimulatory nicotinic mechanism. The repeatedly administered nicotine caused deep hypothermia, and increased the striatal DOPAC content but decreased the 3-MT and HVA contents. The small dose of mecamylamine, which was the only dose found to effectively antagonize the nicotine-induced hypothermia, antagonized the decrease of HVA content. The large but not the small doses of mecamylamine and pempidine antagonized the nicotine-induced increase of DOPAC content but none of the doses studied antagonized the decrease of 3-MT content. Thus it seems that nicotine decreases the 3-MT content by a mechanism distinct from the mechanism mediating the increase of the DOPAC content. The decreased 3-MT content most probably results from desensitization of nicotinic cholinergic receptors (nAChR) and following decrease of cholinergic regulation of nigrostriatal dopaminergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)Archiv für Experimentelle Pathologie und Pharmakologie 09/1988; 338(2):169-73. · 2.65 Impact Factor
Article: Effects of the competitive nicotinic antagonist erysodine on behavior occasioned or maintained by nicotine: comparison with mecamylamine.[show abstract] [hide abstract]
ABSTRACT: The cellular effects of nicotine underlying its addictive liability are thought to be mediated by neuronal nicotinic receptors (nACHRs) in the central nervous system. It is believed that densely expressed beta32-containing nACHRs in the central nervous system are responsible for these actions, but few data are available that can directly assess subtype mediation of nicotine's acute subjective and reinforcing effects. The present study compared the effects of the competitive nACHR antagonist erysodine and the noncompetitive antagonist mecamylamine in rats trained to discriminate or self-administer nicotine. Adult male rats were trained to discriminate 0.4-mg/kg injections of nicotine from vehicle in a two-lever procedure of food-maintained behavior, or to self-administer 0.03-mg/kg injections of nicotine under fixed-ratio 5 or progressive-ratio schedules of reinforcement. Additional rats were trained under a food-maintained procedure of lever pressing. Erysodine (0.3-10 mg/kg) and mecamylamine (0.1-1.0 mg/kg) blocked nicotine discrimination, although only erysodine produced the rightward shift that would be predicted of a competitive antagonist. Erysodine (0.32-32 mg/kg) and mecamylamine (0.32-3.2 mg/kg) also selectively reduced nicotine self-administration on a fixed-ratio schedule and lowered break points on a progressive-ratio schedule. Based on the known affinity of erysodine for alpha4beta2 nACHRs and its selectivity relative to alpha7 and alpha1beta1gammadelta receptors, the present data support a critical role of beta2-containing nACHR constructs in the discriminative and reinforcing actions of nicotine.Psychopharmacologia 03/2000; 148(3):234-42. · 4.08 Impact Factor