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

Abstract

The val allele of the catechol-O-methyltransferase (COMT) val(158)met 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)>or=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.

Figure 1

Visual N-back median reaction time difference scores. Median reaction time difference scores (N-back minus 0-back) for all responses show significant differences between the three genotype groups (Wald χ²(2) = 7.05, P = 0.03). Within the val/val group, there is a significant decrease in average response time during the smoking session for the 3-back condition, compared to abstinence.

Figure 2

Visual N-back working memory task activation. (a) Mean activation for abstinent and smoking sessions identified by a parametric model of increased working memory load (P≤0.05, corrected). Brain rendering performed with CARET. (b) Mean percent signal change (N-back minus 0-back) for the 1-back, 2-back and 3-back contrasts calculated from a priori regions of interest. Abstinence effects differed among the three genotype groups (Wald χ²(2) = 15.06, P = 0.0005).