The Discriminative Stimulus Effects of Nicotine, Epibatidine, and Varenicline in Mice: Involvement of β2 Containing Nicotinic Acetylcholine Receptor Subtypes

Nicotine is a high efficacy β2 containing nicotinic acetylcholine receptor (β2 nAChR) agonist, whereas varenicline has low efficacy at β2 nAChRs. To better understand the receptor pharmacology of varenicline, male C57BL/6J mice (n=8) were trained to discriminate varenicline (3.2 mg/kg s.c.) under an FR10 schedule of food presentation. Separate groups of mice (n=8 per group) were trained to discriminate nicotine (1 mg/kg base weight s.c.) or the β2 nAChR agonist epibatidine (0.0032 mg/kg s.c.). Mice trained with nicotine and epibatidine satisfied the test criteria after a mean of 87 and 89 sessions, respectively, whereas varenicline‐trained mice required significantly more (i.e., 113) sessions. Varenicline was less effective than nicotine and epibatidine in maintaining stimulus control as evidenced by the number of training sessions required between tests. The nicotine and epibatidine dose‐effect functions did not vary as a function of training drug; the functions were steep and characterized by low inter‐subject variability. In contrast, the varenicline dose‐effect functions were shallow and highly variable among mice. Varenicline produced a maximum 63% and 61% drug‐appropriate responding in the nicotine and epibatidine discriminations, respectively. The nAChR antagonist mecamylamine (3.2 mg/kg) antagonized the effects of nicotine, epibatidine, and varenicline. In contrast, the β2 antagonist DHβE (3.2 mg/kg) antagonized the effects of nicotine and epibatidine, but not varenicline. These results suggest that the discriminative stimulus effects of varenicline are not as robust as those of nicotine and epibatidine and are not mediated by β2 nAChRs. *Supported by USPHS grant DA25267