Modulation of nicotine effects on selective attention by DRD2 and CHRNA4 gene polymorphisms

Rationale Pharmacological and genetic modulation of cholinergic nicotinic neurotransmission influence visuospatial attention in humans. Prior studies show that nicotine as well as a single nucleotide polymorphism (SNP) in the gene coding for the alpha 4 subunit of the nicotinic acetylcholine receptor (CHRNA4) modulate visuospatial attention and distractor interference. The CHRNA4 gene synergistically interacts with a polymorphism in the dopaminergic receptor type d2 (DRD2) gene and impacts brain structure and cognition. Objective We aimed to investigate whether CHRNA4 and DRD2 genotypes alter the effects of nicotine on distractor interference. Methods Fifty-eight young healthy non-smokers were geno-typed for CHRNA4 (rs1044396) and DRD2 (rs6277). They received either 7 mg transdermal nicotine or a matched placebo in a double-blind, within-subject design 1 h prior to performing a visual search task with distractors. Results In isolation, DRD2 but not CHRNA4 genotype modulated the effects of nicotine on distractor interference with DRD2 CC carriers showing the strongest reduction of distractor interference after nicotine administration. A further analysis provided additional evidence that this effect was driven by those subjects, who carried at least one C allele in the CHRNA4 gene. Conclusion The effects of nicotine on distractor interference are modulated synergistically by cholinergic and dopaminergic genetic variations. Hence, both genes may contribute to the often reported individual variability in cognitive and neural effects of nicotine.