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Dopaminergic genetic variation moderates the effect of nicotine on cigarette reward

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Abstract

Rationale

Cigarette smoking is influenced by nicotine’s effects on dopaminergic activity in the mesocorticolimbic pathway. This activity appears to be moderated by genetic variation, specifically a variable number tandem repeat (VNTR) polymorphism in the third exon of the dopamine receptor gene (DRD4).

Objective

We examined whether this polymorphism along with three DRD4 single-nucleotide polymorphisms (SNPs: rs936460, rs936461, and rs12280580) moderate the influence of nicotine on subjective responses to cigarettes.

Methods

White, non-Hispanic smokers (n = 96, cigarettes/day ≥15) attended two double-blind, counterbalanced experimental sessions, each preceded by overnight smoking abstinence. Participants smoked four nicotine (8.9 mg) or placebo (1.0 mg) cigarettes per session, with each cigarette followed by completion of the modified Cigarette Evaluation Questionnaire (mCEQ).

Results

We examined the mCEQ composite score via 2 × 2 × 4 ANOVAs with genotype (major homozygotes versus minor carriers) as the between-subject factor and nicotine content and smoking bout as within-subject factors. Although DRD4 VNTR variation did not moderate overall nicotine response, there was a moderation of nicotine response over successive cigarettes. Smokers with fewer than seven repeats for the DRD4 VNTR reported markedly reduced craving, increased satisfaction, and a greater calming effect in response to earlier smoked nicotine cigarettes, whereas those with seven or more repeats did not. In addition, minor carriers for all three DRD4 SNPs displayed blunted overall response to nicotine.

Conclusion

These findings provide support for DRD4 variation as an informative predictor of subjective responses to nicotine. We discuss how these data may lead to improved tailoring of smoking cessation pharmacotherapies.

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Acknowledgments

This work has been supported in part by the Molecular Genomics Core Facility and the Biostatistics Core Facility at the H. Lee Moffitt Cancer Center & Research Institute, a NCI designated Comprehensive Cancer Center (P30-CA76292), as well as by the National Cancer Institute Behavioral Oncology Training Grant (R25CA090314) at Moffitt Cancer Center in Tampa, FL, awarded to Paul Jacobsen, and by grants R21DA027001 and R21DA024226, awarded to David Evans and David Drobes, respectively. The authors would also like to thank Renee Ornduff and Natasha Garcia for their work on this project.

Author contribution

DE and DD were responsible for the original study concept and design. DE and PH were responsible for secondary analysis study concept and design. PH completed data analysis and drafted the manuscript in collaboration with DE. DD and MB provided critical revisions to the manuscript. JP provided genotyping and genetic consultation. HL provided genetic and statistical consultation. All authors contributed to the manuscript and approved final version for publication.

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Authors and Affiliations

  1. Eastern Virginia Medical School, Norfolk, VA, USA

    Paul T. Harrell

  2. Moffitt Cancer Center, Tampa, FL, USA

    Hui-Yi Lin, Jong Y. Park, David J. Drobes & David E. Evans

  3. University of South Florida, Tampa, FL, USA

    Hui-Yi Lin, Jong Y. Park, David J. Drobes & David E. Evans

  4. West Virginia University, Morgantown, WV, USA

    Melissa D. Blank

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  1. Paul T. Harrell
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  2. Hui-Yi Lin
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  5. David J. Drobes
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  6. David E. Evans
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Corresponding author

Correspondence to David E. Evans.

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Funding

This study was funded by NIH grants R21 DA027001 and R21 DA024226.

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Harrell, P.T., Lin, HY., Park, J.Y. et al. Dopaminergic genetic variation moderates the effect of nicotine on cigarette reward. Psychopharmacology 233, 351–360 (2016). https://doi.org/10.1007/s00213-015-4116-6

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  • DOI: https://doi.org/10.1007/s00213-015-4116-6

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