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      Differential cross-tolerance to the effects of nicotinic acetylcholine receptor drugs in C57BL/6J mice following chronic varenicline

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          Abstract

          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.

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          Author and article information

          Journal
          9013016
          20859
          Behav Pharmacol
          Behav Pharmacol
          Behavioural pharmacology
          0955-8810
          1473-5849
          8 February 2021
          August 2019
          17 February 2021
          : 30
          : 5
          : 412-421
          Affiliations
          [a ]Department of Preclinical Pharmacology Program, McLean Hospital, Belmont
          [b ]Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
          [c ]Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida, USA
          Author notes
          Correspondence to Fernando B. de Moura, PhD, Preclinical Pharmacology Program, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA fmoura@ 123456mclean.harvard.edu
          Article
          PMC7887875 PMC7887875 7887875 nihpa1669099
          10.1097/FBP.0000000000000452
          7887875
          30398980
          c7649744-8cb5-4a21-bcd7-3cefbb430ed8
          History
          Categories
          Article

          cytisine,operant responding,hypothermia,cross-tolerance,nicotine,varenicline,epibatidine,tolerance

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