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Research ArticleNeuropharmacology

Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum

Tanuja Bordia, Maya Hrachova, Matthew Chin, J. Michael McIntosh and Maryka Quik
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 327-334; DOI: https://doi.org/10.1124/jpet.112.194852
Tanuja Bordia
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Maya Hrachova
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Matthew Chin
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J. Michael McIntosh
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Maryka Quik
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Abstract

Extensive evidence indicates that varenicline reduces nicotine craving and withdrawal symptoms by modulating dopaminergic function at α4β2* nicotinic acetylcholine receptors (nAChRs) (the asterisk indicates the possible presence of other nicotinic subunits in the receptor complex). More recent data suggest that α6β2* nAChRs also regulate dopamine release and mediate nicotine reinforcement. The present experiments were therefore done to test the effect of varenicline on α6β2* nAChRs and their function, because its interaction with this subtype is currently unclear. Receptor competition studies showed that varenicline inhibited α6β2* nAChR binding (Ki = 0.12 nM) as potently as α4β2* nAChR binding (Ki = 0.14 nM) in rat striatal sections and with ∼20-fold greater affinity than nicotine. Functionally, varenicline was more potent in stimulating α6β2* versus α4β2* nAChR-mediated [3H]dopamine release from rat striatal synaptosomes with EC50 values of 0.007 and 0.086 μM, respectively. However, it acted as a partial agonist on α6β2* and α4β2* nAChR-mediated [3H]dopamine release with maximal efficacies of 49 and 24%, respectively, compared with nicotine. We also evaluated varenicline's action in striatum of monkeys, a useful animal model for comparison with humans. Varenicline again potently inhibited monkey striatal α6β2* (Ki = 0.13 nM) and α4β2* (Ki = 0.19 nM) nAChRs in competition studies. Functionally, it potently stimulated both α6β2* (EC50 = 0.014 μM) and α4β2* (EC50 = 0.029 μM) nAChR-mediated [3H]dopamine release from monkey striatal synaptosomes, again acting as a partial agonist relative to nicotine at both subtypes. These data suggest that the ability of varenicline to interact at α6β2* nAChRs may contribute to its efficacy as a smoking cessation aid.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS 59910, NS 65851]; the National Institutes of Health National Institute on Drug Abuse [Grant DA015663]; and the Tobacco-Related Disease Research Program [Grant 17RT-0119].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.194852.

  • ABBREVIATIONS:

    nAChR
    nicotinic acetylcholine receptor
    CNS
    central nervous system
    α-CtxMII
    α-conotoxin MII
    BSA
    bovine serum albumin.

  • Received March 28, 2012.
  • Accepted April 30, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 2
1 Aug 2012
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Research ArticleNeuropharmacology

Varenicline and α6β2* nAChRs

Tanuja Bordia, Maya Hrachova, Matthew Chin, J. Michael McIntosh and Maryka Quik
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 327-334; DOI: https://doi.org/10.1124/jpet.112.194852

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Research ArticleNeuropharmacology

Varenicline and α6β2* nAChRs

Tanuja Bordia, Maya Hrachova, Matthew Chin, J. Michael McIntosh and Maryka Quik
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 327-334; DOI: https://doi.org/10.1124/jpet.112.194852
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