Differential discriminative-stimulus effects of cigarette smoke condensate and nicotine in nicotine-discriminating rats

Although it is widely accepted that nicotine plays a key role in tobacco dependence, nicotine alone cannot account for all of the pharmacological effects associated with cigarette smoke found in preclinical models. Thus, the present study aimed to determine the differential effects of the interoceptive cues of nicotine alone versus those of cigarette smoke condensate (CSC) in nicotine-trained rats. First, the rats were trained to discriminate nicotine (0.4 mg/kg, subcutaneous [s.c.]) from saline in a two-lever drug discrimination paradigm. Then, to clarify the different neuropharmacological mechanisms underlying the discriminative-stimulus effects in the nicotine and CSC in nicotine-trained rats, either the alpha 4 beta 2 nicotinic acetylcholine receptor (nAChR) antagonist dihydro-beta-erythroidine (DIVE; 0.3-1.0 mg/kg, s.c.) or the alpha 7 nAChR antagonist methyllycaconitine citrate (MLA; 5-10 mg/kg, intraperitoneal [i.p.]) was administered prior to the injection of either nicotine or CSC. Separate set of experiments was performed to compare the duration of action of the discriminative-stimulus effects of CSC and nicotine. CSC exhibited a dose dependent nicotine generalization, and interestingly, 1.0 mg/kg of DH beta E antagonized the discriminative effects of nicotine (0.4 mg/kg) but not CSC (0.4 mg/kg nicotine content). However, pretreatment with MLA had no effect. In the time-course study, CSC had a relatively longer half-life in terms of the discriminative stimulus effects compared with nicotine alone. Taken together, the present findings indicate that CSC has a distinct influence on interoceptive effects relative to nicotine alone and that these differential effects might be mediated, at least in part, by the alpha 4 beta 2, but not the alpha 7, nAChR. (C) 2016 Elsevier B.V. All rights reserved.