Open AccessDifferential cross-tolerance to the effects of nicotinic acetylcholine receptor drugs in C57BL/6J mice following chronic varenicline
Author(s) -
Fernando B. de Moura,
Lance Richard McMahon
Publication year - 2019
Publication title -
behavioural pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 80
eISSN - 1473-5849
pISSN - 0955-8810
DOI - 10.1097/fbp.0000000000000452
Subject(s) - varenicline , cytisine , mecamylamine , pharmacology , nicotine , nicotinic agonist , nicotinic acetylcholine receptor , medicine , chlorisondamine , epibatidine , smoking cessation , partial agonist , anesthesia , agonist , receptor , pathology , blood pressure
Varenicline is a smoking cessation pharmacotherapy with a presumed mechanism of action of partial efficacy at the α4β2 nicotinic acetylcholine receptor (nAChR); however, the extent to which daily varenicline use leads to changes in nAChR sensitivity is unclear. This study examined the consequences of daily varenicline treatment on disruptions in operant responding (i.e. rate-decreasing effects) and hypothermia induced by administration of nicotine, epibatidine, cytisine, and cocaine in C57BL/6J mice. Furthermore, mecamylamine was used to assess the involvement of nAChRs in the effects of varenicline. Mice were trained under a fixed ratio 20 of milk reinforcement, and rectal temperatures were measured after 30 min following drug-administration. Varenicline, nicotine, epibatidine, and cytisine produced dose-dependent decreases in response rate and rectal temperature. Chronic varenicline (30 mg/kg) engendered tolerance to varenicline, but more cross-tolerance to nicotine, for both disruptions in operant responding and hypothermia. Cross-tolerance only developed to the hypothermic effects of epibatidine, and no cross-tolerance developed to any effects of cytisine and cocaine. In varenicline-tolerant mice, mecamylamine did not antagonize the effects of varenicline. The varying magnitudes of tolerance and cross-tolerance among effects and drugs are indicative of a nonuniform nAChR pharmacology in vivo.