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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

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customer support SIMILAR CONTENT BEING VIEWED BY OTHERS NOT ALL SMOKERS ARE ALIKE: THE HIDDEN COST OF SUSTAINED ATTENTION DURING NICOTINE ABSTINENCE Article Open access 28 January 2022

EFFECTS OF PHARMACOLOGICAL AND GENETIC REGULATION OF COMT ACTIVITY IN ALCOHOL USE DISORDER: A RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF TOLCAPONE Article 06 May 2022 RESTING-STATE FUNCTIONAL

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46: 557–567. Article  CAS  Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 * 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 * 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 * Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA E P Wileyto, P Sanborn, K Tang, A A Strasser, R Ray & C Lerman * The

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Google Scholar * C Lerman View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to J Loughead or C Lerman. ADDITIONAL

INFORMATION DISCLOSURE/CONFLICT OF INTEREST The authors do not have any conflicts of interest pertaining to this research. Supplementary Information accompanies the paper on the Molecular

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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 Download citation * Received: 10 October 2008 * Accepted: 11 November 2008 * Published: 09 December 2008 * Issue Date: August 2009 * DOI:

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available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * nicotine * addiction * _COMT_ * neuroimaging * genetics