Differential generalization among nicotinic acetylcholine receptor agonists in nicotine, varenicline, and epibatidine drug discriminations in mice (661.11)

In addition to a nicotine discrimination assay, two novel nicotinic acetylcholine receptor (nAChR) agonist discriminations were established to examine the relative contribution of nAChR agonist efficacy to behavioral effects. Male C57Bl/6J mice were trained to discriminate nicotine (1 mg/kg), the low efficacy nAChR agonist varenicline (3.2 mg/kg), or the high efficacy nAChR agonist epibatidine (0.0056 mg/kg) from saline. Nicotine produced a maximum effect of 86% and 82% drug‐appropriate responding in the nicotine and varenicline discriminations, respectively. In mice trained to discriminate epibatidine, nicotine produced 84% drug‐appropriate responding, but at a dose that reduced the rate of responding to 19% of control. Varenicline produced 95% drug‐appropriate responding in the varenicline discrimination, but only a maximum of 46% and 70% drug‐appropriate responding in the nicotine and epibatidine discriminations, respectively. A t‐test showed that the maximum effect for varenicline was significantly lower (p<0.05) in the nicotine discrimination than in the varenicline discrimination. Epibatidine produced no less than 90% drug‐appropriate responding in all three discriminations. These data suggest that the discriminative stimulus effects of nAChR agonists vary as a function of the efficacy of the training drug. That nicotine only substituted for epibatidine at a dose of nicotine that markedly decreased response rate might suggest that epibatidine and nicotine have overlapping, but not identical, in vivo effects. Grant Funding Source : USPHS DA25267