Abstract Rationale: Nicotine, a tobacco alkaloid, is known to be important in the acquisition and mainte- nance of tobacco smoking. Nornicotine, an active nico- tine metabolite, stimulates nicotinic receptors and may produce psychomotor effects similar to nicotine. Objec- tive: The present study determined the effects of acute and repeated administration of nornicotine on locomotor activity and compared its effects with those of nicotine. Methods: R(+)-Nornicotine (0.3–10 mg/kg), S(–)-nornic- otine (0.3–10 mg/kg), S(–)-nicotine (0.1–1 mg/kg) or sa- line 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 hypoactivity, followed by dose-related hyperactivity. Repeated S(–)-nicotine ad- ministration resulted in tolerance to the hypoactivity and sensitization to the hyperactivity. Subsequent testing fol- lowing a saline injection revealed evidence of condi- tioned hyperactivity. Acute administration of 0.3 mg/kg or 1 mg/kg R(+)- or S(–)-nornicotine produced no effect. Transient hypoactivity was observed at 3 mg/kg and 10 mg/kg R(+)-nornicotine and at 10 mg/kg S(–)-nornic- otine. However, rebound hyperactivity was not observed following acute administration of either nornicotine enantiomer, suggesting that nornicotine-induced psycho- motor effects differ qualitatively from those of S(–)-nico- tine. Repeated R(+)-nornicotine resulted in tolerance to the transient hypoactivity, however hyperactivity was not observed. Repeated S(–)-nornicotine resulted in toler- ance to the hypoactivity and the appearance of hyperac- tivity. Repeated administration of either nornicotine enantiomer resulted in a dose-dependent alteration in re- sponse to a 1 mg/kg S(–)-nicotine challenge, suggesting some commonalities in the mechanism of action. Con- clusion: Nornicotine likely contributes to the neurophar- macological effects of nicotine and tobacco use. Key words Nicotine · Nornicotine · Behavioral sensitization · Locomotor activity · Rat Introduction Cigarette smoking is the number-one health problem accounting for more illness and deaths in the United States than any other factor (Surgeon General’s Report 1988). There are numerous socio-cultural factors that contribute to the high incidence of tobacco smoking in the United States (Schelling 1992). From a psychophar- macological perspective, however, it is now widely rec- ognized that tobacco smoking is maintained due to the presence of the psychostimulant nicotine in the inhalant smoke (Stolerman and Jarvis 1995). In a laboratory set- ting, cigarette smokers will make an operant response to self-administer nicotine intravenously (Henningfield et al. 1983). Evidence for the intrinsic reinforcing property of nicotine includes nicotine self-administration by many animal species on various reinforcement schedules (Goldberg et al. 1981; Corrigall et al. 1992; Donny et al. 1995; Valentine et al. 1997) and nicotine-induced condi- tioned place preference in rats (Fudala et al. 1985; Shoaib et al. 1994). Nicotine discrimination and nicotine self-administration are decreased by the nicotinic recep- tor antagonists mecamylamine or dihydro-β-erythroidine (DHβE) (Stolerman et al. 1984; Corrigall et al. 1994; Shoaib et al. 1997), suggesting nicotinic receptor media- tion of these responses. Consistent with its effects in humans, nicotine has psychostimulant effects in laboratory animals. An acute injection of nicotine to rats produces a biphasic effect on locomotor behavior, characterized by an initial decrease in activity, followed by a period of hyperactivity lasting 1 h or longer (Clarke and Kumar 1983; Clarke 1990). L.P. Dwoskin ( ✉ ) · P.A. Crooks · L. Teng College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA e-mail: ldwoskin@pop.uky.edu Tel.: +1-606-257-4743 Fax: +1-606-257-7564 T.A. Green · M.T. Bardo Department of Psychology, University of Kentucky, Lexington, KY 40506, USA Psychopharmacology (1999) 145:442–451 © Springer-Verlag 1999 ORIGINAL INVESTIGATION Linda P. Dwoskin · Peter A. Crooks · LiHong Teng Thomas A. Green · Michael T. Bardo Acute and chronic effects of nornicotine on locomotor activity in rats: altered response to nicotine Received: 11 January 1999 / Final version: 25 March 1999