Smoking continues to be a major health problem and unfortunately smoking cessation interventions have limited success; the conditioning effects of nicotine and individual differences in tobacco addiction are important factors that underlie this setback. The aim of the current study was to investigate nicotine-induced conditioned place preference (CPP) in male and female rats which were previously exposed to a free choice of oral nicotine or water and showed different preferences for nicotine; subsequently nicotine intake also varied between subjects. Exposure patterns were varied in three experiments to allow for assessing the effect of adult v.s. adolescent exposure. The design of CPP testing enabled testing for the possible confounding effects of withdrawal or tolerance. A total of 150 male and female rats were used in three experiments. The oral nicotine choice was provided for at least six weeks in all experiments. Our results replicate our previous findings that nicotine induces CPP in male, but not female rats not pre-exposed to nicotine. Previous nicotine exposure, irrespective of the amount of nicotine consumed, eliminated the conditioning effects of nicotine in a new context. The diminished CPP response was more pronounced in rats exposed to nicotine as adolescents than those exposed as adults. This reduced responsiveness cannot be explained by tolerance. The neuroplastic changes caused by chronic nicotine administration or the strong conditioning to receiving nicotine in the home cage before CPP testing may underlie the weakened responsiveness. These findings support the well known clinical notion that smoking cessation attempts are more successful in a novel environment, not previously connected with smoking. (C) 2011 Elsevier Inc. All rights reserved.