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Effect of abstinence challenge on brain function and cognition in smokers differs by COMT genotype

Molecular Psychiatry volume 14, pages 820–826 (2009)Cite this article

Abstract

The val allele of the catechol-O-methyltransferase (COMT) val158met polymorphism has been linked with nicotine dependence and with cognitive performance in healthy volunteers. We tested the hypothesis that the val allele is a risk factor for altered brain function and cognition during nicotine abstinence as compared with the normal smoking state. Chronic smokers (n=33) were genotyped prospectively for the COMT polymorphism for balanced selection of met/met, val/met and val/val groups. A visual N-back working memory task was performed during two separate blood oxygen level-dependent (BOLD) functional magnetic resonance imaging sessions in counterbalanced order: (1) smoking as usual, and (2)⩾14 h confirmed abstinence. Significant genotype by session interactions were observed for BOLD signal in right dorsolateral prefrontal cortex (DLPFC; (P=0.0005), left DLPFC (P=0.02) and dorsal cingulate/medial prefrontal cortex (P=0.01) as well as for task reaction time (P=0.03). Smokers with val/val genotypes were more sensitive to the abstinence challenge than carriers of the met allele, with the greatest effects on BOLD signal and performance speed at the highest working memory load. These data suggest a novel brain–behavior mechanism that may underlie the increased susceptibility to nicotine dependence and smoking relapse associated with the COMT val allele. Exploration of the effects of COMT inhibitors as a possible smoking cessation aid in this group may be warranted.

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Acknowledgements

This research was supported by grants from the National Cancer Institute and National Institutes on Drug Abuse (P50CA/DA84718), NIH/NINDS Neuroscience Neuroimaging Center (P30 NS045839) and the Pennsylvania Department of Health. The Department of Health disclaims responsibility for any analyses, interpretations or conclusions.

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Authors and Affiliations

  1. Division of Neuropsychiatry, Department of Psychiatry, Brain Behavior Laboratory, University of Pennsylvania, Philadelphia, PA, USA

    J Loughead, J N Valdez, K Ruparel & R C Gur

  2. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

    J Loughead, E P Wileyto, P Sanborn, K Tang, A A Strasser, R Ray, R C Gur & C Lerman

  3. Transdisciplinary Tobacco Use Research Center, University of Pennsylvania, Philadelphia, PA, USA

    E P Wileyto, P Sanborn, K Tang, A A Strasser, R Ray & C Lerman

  4. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    E P Wileyto, P Sanborn, K Tang, A A Strasser, R Ray & C Lerman

  5. The Philadelphia Veterans Administration Medical Center, Philadelphia, PA, USA

    R C Gur

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Correspondence to J Loughead or C Lerman.

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Loughead, J., Wileyto, E., Valdez, J. et al. Effect of abstinence challenge on brain function and cognition in smokers differs by COMT genotype. Mol Psychiatry 14, 820–826 (2009). https://doi.org/10.1038/mp.2008.132

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