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Multiple nicotine training doses in mice as a basis for differentiating the effects of smoking cessation aids

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Abstract

Rationale

Receptor mechanisms underlying the behavioral effects of clinically used nicotinic acetylcholine receptor agonists have not been fully established.

Objective

Drug discrimination was used to compare receptor mechanisms underlying the effects of smoking cessation aids.

Methods

Separate groups of male C57BL/6J mice discriminated 0.56, 1, or 1.78 mg/kg of nicotine base. Nicotine, varenicline, and cytisine were administered alone, in combination with each other, and in combination with mecamylamine and dihydro-β-erythroidine (DHβE). Midazolam and morphine were tested to examine sensitivity to non-nicotinics.

Results

The ED50 value of nicotine to produce discriminative stimulus effects systematically increased as training dose increased. Varenicline and cytisine did not fully substitute for nicotine and, as compared with nicotine, their ED50 values varied less systematically as a function of nicotine training dose. Morphine did not substitute for nicotine, whereas midazolam substituted for the low and not the higher training doses of nicotine. As training dose increased, the dose of mecamylamine needed to produce a significant rightward shift in the nicotine dose-effect function also increased. DHβE antagonized nicotine in animals discriminating the smallest dose of nicotine. Varenicline did not antagonize the effects of nicotine, whereas cytisine produced a modest though significant antagonism of nicotine.

Conclusions

These results suggest that differences in pharmacologic mechanism between nicotine, varenicline, and cytisine include not only differences in efficacy at a common subtype of nicotinic acetylcholine receptor, but also differential affinity and/or efficacy at multiple receptor subtypes.

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Abbreviations

ANOVA:

Analysis of variance

DHβE:

Dihydro-β-erythroidine

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Acknowledgments and funding

The authors are grateful to C. Rock, D. Schulze, and A. Zaki for excellent technical assistance. This work was supported by the National Institutes of Health National Institute on Drug Abuse [DA25267].

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Authors and Affiliations

  1. Department of Pharmacology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA

    Colin S. Cunningham & Lance R. McMahon

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  1. Colin S. Cunningham
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  2. Lance R. McMahon
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Correspondence to Lance R. McMahon.

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Cunningham, C.S., McMahon, L.R. Multiple nicotine training doses in mice as a basis for differentiating the effects of smoking cessation aids. Psychopharmacology 228, 321–333 (2013). https://doi.org/10.1007/s00213-013-3037-5

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  • DOI: https://doi.org/10.1007/s00213-013-3037-5

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