title: Nicotinergic Modulation of Attention-Related Neural Activity Differentiates Polymorphisms of DRD2 and CHRNA4 Receptor Genes.
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.
authors.affiliation: Biological Psychology, Department of Psychology, European Medical School, Carl-von-Ossietzky Universität Oldenburg, Oldenburg, Germany.
authors.forename: Thomas P K
authors.initials: TP
authors.lastname: Breckel
authors.affiliation: Biological Psychology, Department of Psychology, European Medical School, Carl-von-Ossietzky Universität Oldenburg, Oldenburg, Germany; Research Center Neurosensory Science, Carl-von-Ossietzky Universität Oldenburg, Oldenburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Giessing
authors.affiliation: Biological Psychology, Department of Psychology, European Medical School, Carl-von-Ossietzky Universität Oldenburg, Oldenburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Gieseler
authors.affiliation: Biological Psychology, Department of Psychology, European Medical School, Carl-von-Ossietzky Universität Oldenburg, Oldenburg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Querbach
authors.affiliation: Personality & Biological Psychology, Department of Psychology, University of Bonn, Bonn, Germany; Center for Economics & Neuroscience (CENs), Laboratory of Neurogenetics, University of Bonn, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reuter
authors.affiliation: Biological Psychology, Department of Psychology, European Medical School, Carl-von-Ossietzky Universität Oldenburg, Oldenburg, Germany; Research Center Neurosensory Science, Carl-von-Ossietzky Universität Oldenburg, Oldenburg, Germany; Cluster of Excellence "Hearing4all", Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany.
authors.forename: Christiane M
authors.initials: CM
authors.lastname: Thiel
mesh_terms: D000328:Adult; D001288:Attention / Q000187:drug effects*; D001931:Brain Mapping; D004311:Double-Blind Method; D004843:Epistasis, Genetic; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D015999:Multivariate Analysis; D009538:Nicotine / Q000494:pharmacology*; D010775:Photic Stimulation; D011110:Polymorphism, Genetic; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics*
chemical_list: D009538:Nicotine; D017448:Receptors, Dopamine D2; D011978:Receptors, Nicotinic; C581293:DRD2 protein, human