Varenicline Blocks 2*-nAChR-Mediated Response and Activates 4*-nAChR-Mediated Responses in Mice In Vivo
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Chronic varenicline exposure may lead to nAChR desensitization.
“With respect to a long-term mechanism of action, chronic varenicline exposure may subsequently lead to nAChR desensitization (Ortiz et al., 2012).”
From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Ortiz et al., 2012
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Lindemann, L., Jaeschke, G., Michalon, A., Vieira, E., Honer, M., Spooren, W., Porter, R., Hartung, T., Kolczewski, S., Büttelmann, B., et al. (1909) · JAMA · doi:10.1001/jama.1909.02550020033007 · Cited by 7,865 · see citing works
Drug Metabolism and Disposition
(2014) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.12259_4 · Cited by 2,518 · see citing works
Varenicline: An α4β2 Nicotinic Receptor Partial Agonist for Smoking Cessation
Coe, J. W., Brooks, P. R., Vetelino, M. G., Wirtz, M. C., Arnold, E. P., Huang, J., Sands, S. B., Davis, T. I., Lebel, L. A., Fox, C. B., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm050069n · Cited by 930 · see citing works
Guidelines on nicotine dose selection for in vivo research
Matta, S. G., Balfour, D. J., Benowitz, N. L., Boyd, R. T., Buccafusco, J. J., Caggiula, A. R., Craig, C. R., Collins, A. C., Damaj, M. I., Donny, E. C., et al. (2007) · Psychopharmacology · doi:10.1007/s00213-006-0441-0 · Cited by 824 · see citing works
Self-citationAbnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain
Picciotto, M. R., Zoli, M., Léna, C., Bessis, A., Lallemand, Y., LeNovère, N., Vincent, P., Pich, E. M., Brûlet, P., & Changeux, J.-P. (1995) · Nature · doi:10.1038/374065a0 · Cited by 668 · see citing works
Varenicline Is a Partial Agonist at α4β2 and a Full Agonist at α7 Neuronal Nicotinic Receptors
Mihalak, K. B., Carroll, F. I., & Luetje, C. W. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.025130 · Cited by 558 · see citing works
Rollema, H., Chambers, L. K., Coe, J. W., Glowa, J., Hurst, R. S., Lebel, L. A., Lu, Y., Mansbach, R. S., Mather, R. J., Rovetti, C. C., et al. (2007) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.10.016 · Cited by 533 · see citing works
Orr‐Urtreger, A., Göldner, F. M., Saeki, M., Lorenzo, I., Goldberg, L. B., Biasi, M. D., Dani, J. A., Patrick, J. W., & Beaudet, A. L. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-23-09165.1997 · Cited by 494 · see citing works
Salminen, O., Murphy, K. L., McIntosh, J. M., Drago, J., Marks, M. J., Collins, A. C., & Grady, S. R. (2004) · Molecular Pharmacology · doi:10.1124/mol.65.6.1526 · Cited by 401 · see citing works
Self-citationXu, W., Orr‐Urtreger, A., Nigro, F., Gelber, S. E., Sutcliffe, C. B., Armstrong, D. L., Patrick, J. W., Role, L. W., Beaudet, A. L., & Biasi, M. D. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-21-09298.1999 · Cited by 283 · see citing works
Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis
Mineur, Y. S., & Picciotto, M. R. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.09.004 · Cited by 277 · see citing works
Obach, R. S., Reed‐Hagen, A. E., Krueger, S. S., Obach, B. J., O’Connell, T. N., Zandi, K. S., Miller, S., & Coe, J. W. (2005) · Drug Metabolism and Disposition · doi:10.1124/dmd.105.006767 · Cited by 199 · see citing works
Kuryatov, A., Berrettini, W., & Lindstrom, J. (2011) · Molecular Pharmacology · doi:10.1124/mol.110.066357 · Cited by 171 · see citing works
Rollema, H., Shrikhande, A., Ward, K., Tingley III, F., Coe, J., O'Neill, B., Tseng, E., Wang, E., Mather, R., Hurst, R., et al. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00682.x · Cited by 162 · see citing works
Petersen, D. R., Norris, K. J., & Thompson, J. A. (1984) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(25)07789-x · Cited by 160 · see citing works
Xiao, Y., Fan, H., Musachio, J. L., Wei, Z.-L., Chellappan, S. K., Kozikowski, A. P., & Kellar, K. J. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.027318 · Cited by 141 · see citing works
Rollema, H., Hajós, M., Seymour, P. A., Kozak, R., Majchrzak, M. J., Guanowsky, V., Horner, W. E., Chapin, D. S., Hoffmann, W. E., Johnson, D. E., et al. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.05.033 · Cited by 117 · see citing works
Faessel, H. M., Smith, B. J., Gibbs, M. A., Gobey, J. S., Clark, D. J., & Burstein, A. H. (2006) · The Journal of Clinical Pharmacology · doi:10.1177/0091270006290669 · Cited by 104 · see citing works
Grady, S. R., Drenan, R. M., Breining, S. R., Yohannes, D., Wageman, C. R., Fedorov, N. B., McKinney, S., Whiteaker, P., Bencherif, M., Lester, H. A., et al. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.01.013 · Cited by 98 · see citing works
Self-citationSmith, J. W., Mogg, A. J., Tafi, E., Peacey, E., Pullar, I. A., Szekeres, P. G., & Tricklebank, M. D. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0596-8 · Cited by 94 · see citing works
Turner, J. R., Castellano, L. M., & Blendy, J. A. (2010) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.166280 · Cited by 88 · see citing works
McCallum, S. E., Collins, A. C., Paylor, R. E., & Marks, M. J. (2005) · Psychopharmacology · doi:10.1007/s00213-005-0076-6 · Cited by 72 · see citing works
Self-citationVarenicline Is a Potent Agonist of the Human 5-Hydroxytryptamine3 Receptor
Lummis, S. C. R., Thompson, A. J., Bencherif, M., & Lester, H. A. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.185306 · Cited by 71 · see citing works
Mecamylamine blockade of nicotine responses: Evidence for two brain nicotinic receptors
Collins, A. C., Evans, C. B., Miner, L. L., & Marks, M. J. (1986) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(86)90518-6 · Cited by 67 · see citing works
Self-citationVarenicline for smoking cessation: efficacy, safety, and treatment recommendations
Ebbert, J. O. (2010) · Patient Preference and Adherence · doi:10.2147/ppa.s10620 · Cited by 67 · see citing works
Papke, R. L., Wecker, L., & Stitzel, J. A. (2010) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.164566 · Cited by 67 · see citing works
A test battery for measuring nicotine effects in mice
Marks, M. J., Romm, E., Bealer, S. M., & Collins, A. C. (1985) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(85)90577-5 · Cited by 65 · see citing works
Self-citationMarks, M. J., Robinson, S. F., & Collins, A. C. (1996) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)13086-3 · Cited by 65 · see citing works
Self-citationVarenicline ameliorates nicotine withdrawal-induced learning deficits in C57BL/6 mice.
Raybuck, J. D., Portugal, G. S., Lerman, C., & Gould, T. J. (2008) · Behavioral Neuroscience · doi:10.1037/a0012601 · Cited by 62 · see citing works
Papke, R. L., Trocmé, C., Guendisch, D., Rubaiy, S. A. A. A., & Bloom, S. A. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.177485 · Cited by 61 · see citing works
Pauly, J. R., Grun, E. U., & Collins, A. C. (1990) · Psychopharmacology · doi:10.1007/bf02244047 · Cited by 59 · see citing works
Tritto, T., McCallum, S. E., Waddle, S., Hutton, S. R., Paylor, R. E., Collins, A. C., & Marks, M. J. (2004) · Nicotine & Tobacco Research · doi:10.1080/14622200310001656966 · Cited by 57 · see citing works
Self-citationAnderson, D. J., Bunnelle, W. H., Surber, B. W., Du, J. Y., Surowy, C. S., Tribollet, E., Marguerat, A., Bertrand, D., & Gopalakrishnan, M. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.130062 · Cited by 52 · see citing works
Repérant, C., Pons, S., Dufour, E., Rollema, H., Gardier, A. M., & Maskos, U. (2009) · Neuropharmacology · doi:10.1016/j.neuropharm.2009.10.007 · Cited by 41 · see citing works
Effect of varenicline on the acute and repeated locomotor responses to nicotine in rats
Zaniewska, M., McCreary, A. C., Stefański, R., Przegaliński, E., & Filip, M. (2008) · Synapse · doi:10.1002/syn.20564 · Cited by 32 · see citing works
Cunningham, C. S., & McMahon, L. R. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.12.003 · Cited by 24 · see citing works
Naumenko, V. S., Kondaurova, E. M., & Popova, N. K. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.09.005 · Cited by 24 · see citing works
Ondansetron and fluoxetine reduce sleep apnea in mice lacking monoamine oxidase A
Real, C. C., Seif, I., Adrien, J., & Escourrou, P. (2009) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2009.07.003 · Cited by 20 · see citing works
Carroll, F. I., Yokota, Y., Ma, W., Lee, J. R., Brieaddy, L. E., Burgess, J. P., Navarro, H. A., Damaj, M. I., & Martin, B. R. (2007) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2007.10.027 · Cited by 16 · see citing works
Zambrano, C. A., Marks, M. J., Cassels, B. K., & Maccioni, R. B. (2009) · Neuropharmacology · doi:10.1016/j.neuropharm.2009.05.004 · Cited by 11 · see citing works
Self-citationVarenicline overdose in a teenager – a clinical pharmacology perspective
Rollema, H., Faessel, H. M., & Williams, K. E. (2009) · Clinical Toxicology · doi:10.1080/15563650902970689 · Cited by 6 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Bordia, T., Hrachova, M., Chin, M., McIntosh, J. M., & Quik, M. (2012) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.194852 · Cited by 70 · see citing works
- Authors
- Ortiz, N. C., O'Neill, H. C., Marks, M. J., & Grady, S. R.
- Affiliations
- University of Colorado Boulder (US)
- ORCID
- Marks, M. J.
- Venue
- Nicotine & Tobacco Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-01-12
- Volume
- 14
- Issue
- 6
- Pages
- 711-719
- ISSN
- 1462-2203 (ISSN-L)
- 1469-994X
- PMC
- PMC3356295
- 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
- bronze
- doi.org
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review