Nornicotine pretreatment decreases intravenous nicotine self-administration in rats

Rationale: Nicotine has been shown to be effective as a treatment for reduc ing tobacco dependence. However, few studies have examined the effect of ot her 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 nicot ine self-administration in rats. Methods: Each rat was prepared with an ind welling jugular catheter and trained to self-administer intravenous nicotin e (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) an d assessed for nicotine self-administration. A separate group of rats was m aintained on sucrose reinforced responding and pretreated with nornicotine to determine the specificity of the pretreatment effect. In another group o f 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 s pecific to nicotine self-administration, as this dose did not decrease sucr ose reinforced responding in tolerant animals. In addition, within the dose range tested, the suppressant effect of nornicotine had a twofold longer d uration than that of nicotine (120 versus 60 min). Conclusion: These result s suggest that nornicotine may be an effective treatment for tobacco depend ence.