Acute and chronic effects of nornicotine on locomotor activity in rats: altered response to nicotine

Rationale: Nicotine, a tobacco alkaloid, is known to be important in the ac quisition and maintenance of tobacco smoking. Nornicotine, an active nicoti ne metabolite, stimulates nicotinic receptors and may produce psychomotor e ffects similar to nicotine. Objective: The present study determined the eff ects of acute and repeated administration of nornicotine on locomotor activ ity and compared its effects with those of nicotine. Methods: R(+)-Nornicot ine (0.3-10 mg/kg), S(-)-nornicotine (0.3-10 mg/kg), S(-)-nicotine (0.1-1 m g/kg) or saline was administered s.c, to rats acutely or repeatedly (eight injections at 48-h intervals). Activity was recorded for 50 min immediately after each injection. Results: S(-)-Nicotine produced transient hypoactivi ty, followed by dose-related hyperactivity. Repeated S(-)-nicotine administ ration resulted in tolerance to the hypoactivity and sensitization to the h yperactivity. Subsequent testing following a saline injection revealed evid ence of conditioned hyperactivity. Acute administration of 0.3 mg/kg or 1 m g/kg R(+)- or S(-)-nornicotine produced no effect. Transient hypoactivity w as observed at 3 mg/kg and 10 mg/kg R(+)-nornicotine and at 10 mg/kg S(-)-n ornicotine. However, rebound hyperactivity was not observed following acute administration of either nornicotine enantiomer, suggesting that nornicoti ne-induced psychomotor effects differ qualitatively from those of S(-)-nico tine. Repeated R(+)-nornicotine resulted in tolerance to the transient hypo activity, however hyperactivity was not observed. Repeated S(-)-nornicotine resulted in tolerance to the hypoactivity and the appearance of hyperactiv ity. Repeated administration of either nornicotine enantiomer resulted in a dose-dependent alteration in response to a 1 mg/kg S(-)-nicotine challenge , suggesting some commonalities in the mechanism of action. Conclusion: Nor nicotine likely contributes to the neuropharmacological effects of nicotine and tobacco use.