Association of abstinence-induced alterations in working memory function and COMT genotype in smokers
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The common methionine (met) for valine (val) at codon 158 (val158met) polymorphism in the catechol-O-methyltransferase (COMT) gene has been associated with nicotine dependence, alterations in executive cognitive function, and abstinence-induced working memory deficits in smokers.
We sought to replicate the association of the COMT val allele with abstinence-induced alterations in working memory-related activity in task-positive (executive control) and task-negative (default mode network) regions.
Forty smokers (20 val/val and 20 met/met) performed an N-back task while undergoing blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) on two separate occasions: following 72 h of confirmed abstinence and during smoking as usual. An independent sample of 48 smokers who completed the identical N-back task during fMRI in smoking vs. abstinence for another study was used as a validation sample.
Contrary to expectations, genotype by session interactions on BOLD signal in executive control regions (dorsolateral prefrontal cortex and dorsal cingulate/medial prefrontal cortex) revealed significant abstinence-induced reductions in the met/met group, but not the val/val group. Results also revealed that val/val smokers may exhibit less suppression of activation in task-negative regions such as the posterior cingulate cortex during abstinence (vs. smoking). These patterns were confirmed in the validation sample and in the whole-brain analysis, though the regions differed from the a priori regions of interest (ROIs) (e.g., precuneus, insula).
The COMT val158met polymorphism was associated with abstinence-related working memory deficits in two independent samples of smokers. However, inconsistencies compared to prior findings and across methods (ROI vs. whole-brain analysis) highlight the challenges inherent in reproducing results of imaging genetic studies in addiction.
KeywordsSmoking Nicotine COMT Genetic fMRI Cognition Working memory
This research was supported by grants R03 DA027438 (CL) and R01 DA026849 (CL) and pilot funding from UL1 RR024134 (RLA). The NIH had no further role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
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