Monoamine oxidase inhibition dramatically prolongs the duration of nicotine withdrawal-induced place aversion

Background: Long-lasting effects of withdrawal from nicotine are hypothesized to contribute to relapse and persistence of tobacco habits, and significant evidence supports a role of monoamine oxidase inhibitors (MAOI) contained in cigarette smoke as potent modulators of the rewarding effects of tobacco. Methods: With quantification of somatic signs of withdrawal and the place aversion conditioning paradigm, we assessed the effects of MAOI pretreatment on both somatic and aversive motivational components of mecamylamine-induced nicotine withdrawal in rats rendered dependent on nicotine by the subcutaneous implantation of osmotic minipumps (vehicle or nicotine tartrate 9 mg/kg/day). Results: In nicotine-infused rats, mecamylamine induced a place aversion that lasted 6 weeks. When nicotine-infused rats were also treated with a MAOI, mecamylamine-induced conditioned place aversion persisted for at least 8 months of abstinence. The MAOI treatment slightly decreased ratings of somatic signs induced by mecamylamine administration but had no effect on the threshold or the magnitude of mecamylamine-induced conditioned place aversion. Conclusions: These results show that MAOI pretreatment induces a long-lasting conditioned placed aversion associated with nicotine withdrawal, possibly through a potentiation of learning and memory process, and provides some indications on protracted abstinence that might be useful for delineating the neurobiological substrate of relapse.