A Rat Model of Cigarette Smoke Abuse Liability

We sought to develop a rat model of cigarette smoke exposure (CSE) that created cotinine serum levels comparable to those of smokers and induced conditioned place preference (CPP) suggestive of cigarette smoke abuse liability. Rats were exposed to sidestream cigarette smoke delivered semicontinuously for 2 periods of 20 (group S20), 40 (group S40), or 60 (group S60) min daily for 12 wk. Serum cotinine concentration in blood samples was determined at 1 and 20 h after CSE. A biased (black versus white chamber) CPP paradigm was used. In the high CSE group (group S60), serum cotinine at 1 h (250 to 300 ng/mL) was comparable to average cotinine levels reported for addicted smokers (around 300 ng/mL). Cotinine levels at 20 h after CSE were higher than the smoker–nonsmoker cut-off value (greater than 14 ng/mL) in all smoking groups, with the S60 group having the highest levels. All rats preferred the black chamber to the white chamber during the preexposure CPP test. The time spent in the white chamber was increased compared with 0-wk values in group S40 at 8 wk, group S60 at 4 and 8 wk, and the control group at 4 and 8 wk but not at 12 wk; however, the shift in CPP was significantly higher at 8 wk in group S60 compared with other groups. In conclusion, interrupted 2-h daily CSE for 8 wk induced serum cotinine levels in rats comparable to those of smokers and induced CPP suggestive of cigarette smoke abuse liability.Abbreviations: CPP, conditioned place preference; CSE, cigarette smoke exposureThe devastating consequences of smoking on health have been studied extensively in numerous clinical and animal studies over time. This chronic habit leads to dependence on tobacco smoke, with nicotine, a main active ingredient of tobacco products, being recognized as the basic addictive substance.³²The known health benefits of smoking cessation motivate smokers to quit tobacco use. However, unaided efforts usually are unsuccessful, resulting in smoking relapse. The fight against nicotine addiction may be undermined by potential weight gain after smoking cessation, potentially discouraging those attempting to quit smoking and contributing to relapse. During the past few years, research has been focused on 2 main areas of interest toward this direction: understanding the underlying biologic mechanisms related to nicotine addiction to effectively design therapeutic strategies to support those who wish to quit smoking and investigating the hormonal and molecular mechanisms responsible for weight gain after smoking cessation.So far, animal models used to study the consequences of smoking cessation involved the administration of nicotine as a sole agent until addiction was achieved.²³ However, nicotine-administration models do not completely represent the toxic and addictive effects of cigarette smoke, given that smoke contains more than 4000 chemicals whose actions or coactions have not been thoroughly evaluated yet.¹ Cigarette smoke exposure (CSE) animal models have been used in studies investigating the metabolic changes conferred by smoking^10-12 but not in those after its cessation. In toxicity studies, animals are exposed to tobacco smoke for various periods, which depend on the side effect under investigation.^18,25,27 Smoke exposure timetables usually do not involve weekends for practical reasons, and addiction of animals to tobacco smoke is not assessed in current models.In our opinion, an ideal animal model of cigarette smoke abuse liability suitable for the study of smoking cessation resembles the clinical situation in terms of chronic daily inhalation of cigarette smoke sufficient to attain blood nicotine levels comparable to those of smokers and in cessation of the CSE period after achieving tobacco smoke abuse liability. In the present project, we sought to establish such a model in rats by defining the daily timetable of CSE to induce serum levels of cotinine, nicotine''s major proximate metabolite, comparable to those of smokers and by determining the minimum total CSE period required to induce abuse liability to cigarette smoke. We assessed the CSE period by using a biased conditioned place preference (CPP) paradigm.⁸