title: Differential antagonism and tolerance/cross-tolerance among nicotinic acetylcholine receptor agonists: scheduled-controlled responding and hypothermia in C57BL/6J mice.
abstract: The tobacco-dependence pharmacotherapies varenicline and cytisine act as partial α4β2 nAChR agonists. However, the extent to which α4β2 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 α4β2 nAChR antagonist dihydro-β-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 (1 mg/kg), but only the effects of nicotine and epibatidine were antagonized by dihydro-β-erythroidine (3.2 mg/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.
authors.affiliation: Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Fernando B
authors.initials: FB
authors.lastname: de Moura
authors.forename: Lance R
authors.initials: LR
authors.lastname: McMahon
mesh_terms: D000818:Animals; D003042:Cocaine; D003216:Conditioning, Operant / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006979:Hyperthermia, Induced / Q000379:methods*; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D018733:Nicotinic Antagonists / Q000627:therapeutic use*; D012055:Reinforcement Schedule; D014029:Tobacco Use Disorder / Q000628:therapy*
chemical_list: D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D008464:Mecamylamine; D003042:Cocaine