Cannabinoid receptor 1 (CNR1) gene variant moderates neural index of cognitive disruption during nicotine withdrawal

Abstract

Nicotine withdrawal-related disruption of cognitive control may contribute to the reinforcement of tobacco use. Identification of gene variants that predict this withdrawal phenotype may lead to tailored pharmacotherapy for smoking cessation. Variation on the cannabinoid receptor 1 gene (CNR1) has been related to nicotine dependence, and CNR1 antagonists may increase attention and memory functioning. We targeted CNR1 variants as moderators of a validated neural marker of nicotine withdrawal-related cognitive disruption. CNR1 polymorphisms comprising the 'TAG' haplotype (rs806379, rs1535255 and rs2023239) were tested independently, as no participants in this sample possessed this haplotype. Nicotine withdrawal-related cognitive disruption was indexed as increased resting electroencephalogram (EEG) alpha-1 power density across 17 electrodes. Seventy-three Caucasian Non-Hispanic smokers (≥15 cigarettes per day) visited the laboratory on two occasions following overnight smoking/nicotine deprivation. Either two nicotine or two placebo cigarettes were smoked prior to collecting EEG data at each session. Analyses showed that rs806379 moderated the effects of nicotine deprivation increasing slow wave EEG (P = 0.004). Smokers homozygous for the major allele exhibited greater nicotine withdrawal-related cognitive disruption. The current findings suggest potential efficacy of cannabinoid receptor antagonism as a pharmacotherapy approach for smoking cessation among individuals who exhibit greater nicotine withdrawal-related cognitive disruption.

Keywords: Alpha-1; CNR1; EEG; ERP; cannabinoid; cognitive control; genetics; nicotine withdrawal; smoking.

Figure 1.. Alpha-1 power density value differences for rs806379

Each bar represents the difference in estimated alpha-1 power density value means for the deprivation and satiation conditions as generated by a mixed model analysis. Each analysis included condition, rs806379, and their interaction along with age, session, hemisphere, session x rs806379, hemisphere x rs806379, and condition × hemisphere × rs806379. Those with the major allele homozygote showed a significantly greater difference between deprivation and satiation than did those with the minor allele for 5 of the 8 cortical regions (*, p<.025). One other cortical region exhibited a marginally significant difference (o, p=.030).