Nicotinergic Modulation of Attention-Related Neural Activity Differentiates Polymorphisms of DRD2 and CHRNA4 Receptor Genes

<div><p>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.</p></div

Visual cueing paradigm (A) and behavioural results (B).

<p><b>A.</b> Scheme of the three task conditions; valid (120), invalid (30), catch (20), and zero (50, no cue and no target, not depicted) trials were presented in randomized order with a SOA of 2000 ms. <b>B.</b> Difference of the validity effect (slowing of RTs due to invalidly cued trials as compared to valid trials) between nicotine and placebo. The CHRNA4 C+ and DRD2 T- genotype group shows a significant benefit from nicotine. The significant three-way interaction of <i>genotype group</i> x <i>treatment</i> x <i>condition</i> as displayed in the current figure was identified by post-hoc ANOVAs to be driven by the <i>genotype group</i> x <i>treatment</i> interaction during invalid trials.</p

Identified brain regions contributing to genotype classification.

<p>¹ Center of gravity coordinate of the clusters.</p><p>² Only clusters that exceeded the voxel extent threshold of k≥40 are reported.</p><p>³ Clusters showing increased (+) or decreased (-) BOLD levels under nicotine (p≤0.05) for each genotype group (CHRNA4 / DRD2) during invalid trials. Post-hoc tests of mean cluster BETA values; tendencies (p≤0.1) are indicated by rectangle brackets.</p><p>Identified brain regions contributing to genotype classification.</p