Abstract
Cognitive and neuronal effects of nicotine show high interindividual variability. Recent findings indicate that genetic variations that affect the cholinergic and dopaminergic neurotransmitter system impact performance in cognitive tasks and effects of nicotine. The current pharmacogenetic functional magnetic resonance imaging (fMRI) study aimed to investigate epistasis effects of CHRNA4/DRD2 variations on behavioural and neural correlates of visuospatial attention after nicotine challenge using a data driven partial least squares discriminant analysis (PLS-DA) approach. Fifty young healthy non-smokers were genotyped for CHRNA4 (rs1044396) and DRD2 (rs6277). They received either 7 mg transdermal nicotine or a matched placebo in a double blind within subject design prior to performing a cued target detection task with valid and invalid trials. On behavioural level, the strongest benefits of nicotine in invalid trials were observed in participants carrying both, the DRD2 T- and CHRNA4 C+ variant. Neurally, we were able to demonstrate that different DRD2/CHRNA4 groups can be decoded from the pattern of brain activity in invalid trials under nicotine. Neural substrates of interindividual variability were found in a network of attention-related brain regions comprising the pulvinar, the striatum, the middle and superior frontal gyri, the insula, the left precuneus, and the right middle temporal gyrus. Our findings suggest that polymorphisms in the CHRNA4 and DRD2 genes are a relevant source of individual variability in pharmacological studies with nicotine.
Highlights
Nicotine acts as stimulant of the cholinergic system and plays an important role in cognitive functions, especially attentional processing [1, 2]
These findings show that subjects with the prevalent s CHRNA4 C+ / dopaminergic D2 receptor (DRD2) T+ genotype mainly show reductions of BOLD activity in parietal, frontal, and temporal brain regions in invalid trials under nicotine, i.e. the effect reported in many prior studies [24, 38,39,40].The findings further suggest that overall BOLD modulation under nicotine is generally stronger
We investigated if gene by gene interactions of variations in CHRNA4 and DRD2 genes impact the effects of nicotine on reorienting visuospatial attention
Summary
Nicotine acts as stimulant of the cholinergic system and plays an important role in cognitive functions, especially attentional processing [1, 2]. Genetic variants in the genes coding for the α4 subunit of the cholinergic nicotinic receptor (CHRNA4) or the dopaminergic D2 receptor (DRD2) are associated with smoking behaviour on the one hand and with visuospatial attention and memory processes on the other hand which may be relevant for personalized treatment of nicotine addiction and cognitive dysfunction [4, 6]. Allelic variants in the DRD2 gene (SNP rs#6277), which mediate D2 receptor density in the brain [11, 12], have been associated with working memory [13,14,15], impulsivity [16]; everyday cognitive failure [17] and performance in the Wisconsin Card Sorting Test [18]. Two studies by Markett and colleagues provide evidence for epistasis effects (gene by gene interaction effects) of DRD2 and CHRNA4 polymorphisms on working memory performance and striatal gray matter volume [14, 19]
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