Dataset Information

Association of abstinence-induced alterations in working memory function and COMT genotype in smokers.

ABSTRACT: The common methionine (met) for valine (val) at codon 158 (val(158)met) 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 val(158)met 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.

SUBMITTER: Ashare RL

PROVIDER: S-EPMC3840089 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Association of abstinence-induced alterations in working memory function and COMT genotype in smokers.

Ashare Rebecca L RL Valdez Jeffrey N JN Ruparel Kosha K Albelda Benjamin B Hopson Ryan D RD Keefe John R JR Loughead James J Lerman Caryn C

Psychopharmacology 20130705 4

<h4>Rationale</h4>The common methionine (met) for valine (val) at codon 158 (val(158)met) 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.<h4>Objectives</h4>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-ne ...[more]

PMID: 23828159

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Project description:The present study examined how a gene related to functioning of the dopaminergic system, catechol-O-methyltransferase (COMT), and estradiol were related to brain functioning in healthy postmenopausal women. Participants were 118 healthy, cognitively normal postmenopausal women between the ages of 50-60 years. All women provided a blood sample for COMT and estradiol analyses and underwent a magnetic resonance imaging scan. Working memory performance and related brain activation were measured with BOLD functional magnetic resonance imaging during the N-back task. Results were examined across each COMT genotype and a median split was performed on the circulating estradiol levels to create high and low estradiol groups for each genotype. COMT genotype and estradiol level were hypothesized to be proxy measures for brain dopamine levels with the Met/Met and high estradiol group having the most dopamine and Val/Val and low estradiol group having the least dopamine. The functional magnetic resonance imaging results showed that the N-back task activated the expected bilateral frontal and bilateral parietal working memory network. However, no main effects of COMT genotype or estradiol group were found. There was COMT-estradiol interaction found in a small area of decreased activation in the right precentral gyrus (Brodmann Area 6) that was related to the increasing hypothesized dopamine level. Specifically, women with a Met/Met genotype in the high estradiol group had the least activation in this frontal lobe working memory region. Women with a Val/Val genotype in the low estradiol group had greater activation in this region relative to the other groups. Performance on the N-back task did not show any group differences. These data indicate that after menopause COMT genotype and potentially the menopause-related changes to the dopaminergic system are not related to cognition. Future studies should examine how the relationship between COMT, estradiol, and cognition around the menopause transition as there appear to be differences in this relationship for premenopausal and postmenopausal women.

Project description:BackgroundDespite the widespread use of oral contraceptives (OCs), and the well-documented influence of estrogens, notably 17β-estradiol (E2), on cognition, research relating OCs to working memory is limited and mixed. Two factors may contribute to these mixed findings: 1) pharmacokinetics of oral contraceptives, which drive fluctuations in synthetic hormone levels; and 2) genetic polymorphisms related to dopamine degradation and working memory, which interact with E2. This research investigated whether the pharmacokinetics of oral contraceptives, in concert with the single nucleotide polymorphism (Val158Met; rs4680) of the catechol-o-methyltransferase gene (COMT), influence working memory performance.MethodsUniversity-age women taking and not taking OCs were tested for working memory and genotyped for COMT. If they were not taking OCs (n = 62), sessions occurred in the early follicular (low E2) and late follicular (high E2) phase. If they were taking OCs (n = 52), sessions occurred 1-2 hours after (high ethinyl estradiol, EE) and ~24 hours after (low EE) pill ingestion. Working memory was tested using the N-back, AX-CPT, Digit Span, and Digit Ordering Tasks. Data were analyzed using multilevel models with estrogen condition, COMT, and group as predictors, controlling for mood and practice effects.ResultsFor women taking OCs, time of pill ingestion did not influence performance. However, the subgroup with COMT val/val (low dopamine) were less accurate on 2-back lure trials than those with COMT met/met (high dopamine). For women not taking OCs, cycle phase moderated COMT's influence on lure accuracy. When compared, women taking OCs had higher AX-CPT proactive control indices than those not taking OCs.ConclusionThese findings suggest that oral contraceptives are not detrimental for young women's working memory and that they may increase proactive control. The more pronounced effects of COMT in women taking OCs suggests that, in women taking OCs, suppressed endogenous E2-not fluctuating EE levels-may be more relevant for working memory. Future studies are needed to differentiate effects of endogenous versus synthetic estrogens on working memory.

Dataset Information

Association of abstinence-induced alterations in working memory function and COMT genotype in smokers.

Publications

Association of abstinence-induced alterations in working memory function and COMT genotype in smokers.

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