Cited by 22Nicotinic Acetylcholine Receptors StudySmoking Behavior and CessationNeuroscience and Neuropharmacology Research

Varenicline Blocks 2*-nAChR-Mediated Response and Activates 4*-nAChR-Mediated Responses in Mice In Vivo

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Ortiz, N. C., O'Neill, H. C., Marks, M. J., Grady, S. R.·2012·Nicotine & Tobacco Research

Abstract

INTRODUCTION: The smoking cessation aid, varenicline, has higher affinity for the alpha4beta2-subtype of the nicotinic acetylcholine receptor (α4β2*-nAChR) than for other subtypes of nAChRs by in vitro assays. The mechanism of action of acute varenicline was studied in vivo to determine (a) subtype activation associated with physiological effects and (b) dose relationship as an antagonist of nicotine. METHODS: Acute doses of saline, nicotine, and varenicline were given to mice, and locomotor depression and hypothermia were measured. Subunit null mutant mice as well as selective antagonists were used to study mode of action of varenicline as an agonist. Varenicline as an antagonist of nicotine was also investigated. RESULTS: Varenicline evokes locomotor depression and hypothermia at higher doses than necessary for nicotine. Null mutation of the α7- or β2-nAChR subunit did not decrease the effectiveness of varenicline; however, null mutation of the β4 subunit significantly decreased the magnitude of the varenicline effect. Effects of the highest dose studied were blocked by mecamylamine (general nAChR antagonist) and partially antagonized by hexamethonium (largely peripheral nAChR antagonist). No significant block was seen with ondansetron antagonist of 5-hydroxytryptamine 3 receptor. Using a dose of nicotine selective for β2*-nAChR subtype effects with these tests, dose-dependent antagonism by varenicline was seen. Effective inhibitory doses were determined and appear to be in a range consistent with binding affinity or desensitization of β2*-nAChRs. CONCLUSIONS: Varenicline acts as a functional antagonist of β2*-nAChRs, blocking certain effects of nicotine. At higher doses, varenicline is an agonist of β4*-nAChRs producing physiological changes in mice.

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Authors
Ortiz, N. C., O'Neill, H. C., Marks, M. J., & Grady, S. R.
Affiliations
University of Colorado Boulder (US)
Venue
Nicotine & Tobacco Research
Published
2012-01-12
Volume
14
Issue
6
Pages
711-719
ISSN
  • 1462-2203 (ISSN-L)
  • 1469-994X
OpenAlex
W2117666501
Cited by
22
References
41
Citations by year
2026: 3 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 1 · 2015: 1 · 2014: 3 · 2013: 2 · 2012: 4
FWCI
1.42
Type
journal article
Language
en
Open access
Locations
  • Nicotine & Tobacco Research (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute on Drug Abuse (U19DA019375, P30DA015663)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
varenicline, alpha4beta2 nAChR, beta2 nAChR, nicotine antagonism, receptor agonism, locomotor depression, hypothermia, smoking cessation, mecamylamine, hexamethonium, dose-response relationship
MeSH terms
Varenicline, Animals, Benzazepines, Dose-Response Relationship, Drug, Female, Genotype, Hypothermia, Male, Mecamylamine, Mice, Inbred C57BL, Motor Activity, Mutation, Nerve Tissue Proteins, Nicotine, Quinoxalines, Receptors, Nicotinic, Ondansetron, Nicotinic Agonists, Nicotinic Antagonists, Hexamethonium, Inhibitory Concentration 50, Receptors, Serotonin, 5-HT3, Mice

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