Nornicotine pretreatment decreases intravenous nicotine self-administration in rats

Rationale: Nicotine has been shown to be effective as a treatment for reducing tobacco dependence. However, few studies have examined the effect of other nicotinic agonists to determine if they can also decrease nicotine self-administration. Objective: The present study determined if nornicotine, a tobacco alkaloid and major nicotine metabolite in brain, could reduce nicotine self-administration in rats. Methods: Each rat was prepared with an indwelling jugular catheter and trained to self-administer intravenous nicotine (0.03 mg/kg per infusion). After nicotine self-administration stabilized, rats were pretreated with either (-)-nicotine (0, 0.1, 0.3, and 1.0 mg/kg free base) or (+/-)-nornicotine (0, 1, 3, 5.6, and 10.0 mg/kg free base) and assessed for nicotine self-administration. A separate group of rats was maintained on sucrose reinforced responding and pretreated with nornicotine to determine the specificity of the pretreatment effect. In another group of rats, the time course of the pretreatment effect of either (-)-nicotine (0.56 and 1.0 mg/kg) or (+/-)-nornicotine (5.6 and 10.0 mg/kg) was examined. Results: Nicotine and nornicotine each produced a dose-dependent decrease in nicotine self-administration. Furthermore, the decrease in nicotine self-administration in response to the 5.6 mg/kg nornicotine pretreatment was specific to nicotine self-administration, as this dose did not decrease sucrose reinforced responding in tolerant animals. In addition, within the dose range tested, the suppressant effect of nornicotine had a twofold longer duration than that of nicotine (120 versus 60 min). Conclusion: These results suggest that nornicotine may be an effective treatment for tobacco dependence.