TY - JOUR
T1 - Differential antagonism and tolerance/cross-tolerance among nicotinic acetylcholine receptor agonists
T2 - Scheduled-controlled responding and hypothermia in C57BL/6J mice
AU - De Moura, Fernando B.
AU - McMahon, Lance R.
N1 - Funding Information:
The authors would like to acknowledge Julia Threadgill and Morgan Cocke for technical support, and Ursula Villarreal-Moura for editorial assistance. Funding: This research was supported by the National Institutes of Health and an ROI grant DA25267.
Publisher Copyright:
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2016/4
Y1 - 2016/4
N2 - 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.
AB - 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.
KW - Cross-tolerance
KW - Cytisine
KW - Dihydro-β-erythroidine
KW - Epibatidine
KW - Hypothermia
KW - Mecamylamine
KW - Nicotine
KW - Simple-schedule responding
KW - Tolerance
KW - Varenicline
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U2 - 10.1097/FBP.0000000000000233
DO - 10.1097/FBP.0000000000000233
M3 - Article
C2 - 26910582
AN - SCOPUS:84959094189
VL - 27
SP - 240
EP - 248
JO - Behavioural Pharmacology
JF - Behavioural Pharmacology
SN - 0955-8810
IS - 2-3
ER -