Differential antagonism and tolerance/cross-tolerance among nicotinic acetylcholine receptor agonists: scheduled-controlled responding and hypothermia in C57BL/6J mice

The tobacco-dependence pharmacotherapies varenicline and cytisine act as partial 42 nAChR agonists. However, the extent to which 42 nicotinic acetylcholine receptors (nAChRs) mediate their in-vivo effects remains unclear. Nicotine, varenicline, cytisine, and epibatidine were studied in male C57BL/6J mice for their effects on rates of fixed ratio responding and rectal temperature alone and in combination with the nonselective nAChR antagonist mecamylamine and the 42 nAChR antagonist dihydro--erythroidine. The effects of nicotine, varenicline, cytisine, epibatidine, and cocaine were assessed before and during chronic nicotine treatment. The rate-decreasing and hypothermic effects of nicotine, varenicline, cytisine, and epibatidine were antagonized by mecamylamine (1mg/kg), but only the effects of nicotine and epibatidine were antagonized by dihydro--erythroidine (3.2mg/kg). Chronic nicotine produced 4.7 and 5.1-fold rightward shifts in the nicotine dose-effect functions to decrease response rate and rectal temperature, respectively. Nicotine treatment decreased the potency of epibatidine to decrease response rate and rectal temperature 2.2 and 2.9-fold, respectively, and shifted the varenicline dose-effect functions 2.0 and 1.7-fold rightward, respectively. Cross-tolerance did not develop from nicotine to cytisine. These results suggest that the in-vivo pharmacology of tobacco cessation aids cannot be attributed to a single nAChR subtype; instead, multiple receptor subtypes differentially mediate their effects. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.