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Baseline Expression of α4β2* Nicotinic Acetylcholine Receptors Predicts Motivation to Self-administer Nicotine

  • Bernard Le Foll
    Correspondence
    Address reprint requests to Bernard Le Foll, M.D., Ph.D., C.C.F.P., Head, Translational Addiction Research Laboratory, University of Toronto, Centre for Addiction and Mental Health, 33 Russell Street, Toronto, Canada M5S 2S1
    Affiliations
    Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada

    Preclinical Pharmacology Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
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  • Svetlana I. Chefer
    Affiliations
    Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
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  • Alane S. Kimes
    Affiliations
    Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
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  • Dean Shumway
    Affiliations
    Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
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  • Elliot A. Stein
    Affiliations
    Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
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  • Alexey G. Mukhin
    Affiliations
    Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland

    Center for Nicotine and Smoking Cessation Research , Duke University Medical Center, Durham, North Carolina
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  • Steven R. Goldberg
    Affiliations
    Preclinical Pharmacology Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland
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Published:December 19, 2008DOI:https://doi.org/10.1016/j.biopsych.2008.09.036

      Background

      Marked interindividual differences in vulnerability to nicotine dependence exist, but factors underlying such differences are not well understood. The midbrain α4β2* subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediation of the reinforcing effects of nicotine responsible for dependence. However, no study has been performed evaluating the impact of interindividual differences in midbrain nAChR levels on motivation to self-administer nicotine.

      Methods

      Baseline levels of α4β2* nAChRs were measured using 2-[18F]fluoro-A-85380 (2-FA) and positron emission tomography (PET) in five squirrel monkeys. Motivation to self-administer nicotine (number of lever presses) was subsequently measured using a progressive-ratio (PR) schedule of reinforcement.

      Results

      Greater motivation to self-administer nicotine was associated with lower levels of midbrain nAChRs.

      Conclusions

      The results suggest that level of expression of nAChRs is a contributing factor in the development of nicotine dependence. Similarly, it has been previously shown that low levels of dopamine D2 receptors (DRD2) are associated with a higher preference for psychostimulant use in humans and nonhuman primates. Together, results from these PET studies of dopaminergic and nicotinic cholinergic transmission suggest that an inverse relationship between the availability of receptors that mediate reinforcement and the motivation to take drugs exists across different neurotransmitter systems.

      Key Words

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