Auditory event-related potentials (P3a, P3b) and genetic variants within the dopamine and serotonin system in healthy females

The late positive components of the human event-related brain potential comprise electrocortical reflections of stimulus-driven attentional capture (the anteriorly distributed P3a) and top-down control detection of relevant events (the posteriorly distributed P3b). As of yet, the neuropharmacologic and neurogenetic origin of the P3a and P3b is not fully understood. In this study, we address the contribution of dopaminergic and serotoninergic mechanisms. Sixty healthy females completed an active auditory novelty oddball paradigm while EEG was recorded. In all subjects, genetic polymorphisms within the dopamine system (dopamine transporter [DAT1], catecholamine-O-methyltransferase val158met [COMT val158met]) and the serotonin system (serotonin transporter [5HTTLPR]) were assessed. Across genotypes, novels (relative to standards) elicited a fronto-centrally distributed P3a, and targets (relative to standards) a parieto-centrally distributed P3b. Genotypes effects were observed for both P3a (COMT, 5HTTPLR) and P3b (DAT1, COMT, 5HTTLPR) only at prefrontal electrode location (Fz). Specifically, the frontal P3a was enhanced in COMT met/met homozygotes, but not in DAT1 9R. The target-related P3b was enhanced in COMT met/met and DAT1 9R relative to its genetic counterparts, but only at frontal electrodes. This 'anteriorized' enhancement may reflect either an additional frontal component in the target-related P3 dependent on dopamine, or a more subtle shift in the neural ensemble that generates the target-related P3. Results for 5HTTLPR short allele homozygotes mimicked those in COMT met/met homozygotes. In all, the present findings suggest involvement of frontal-cortical dopaminergic and serotoninergic mechanisms in bottom-up attentional capture (COMT val158met, 5HTTLPR), with an additional top-down component sensitive to striatal signals (DAT1).

[1]  J L Kenemans,et al.  Event-related potentials and secondary task performance during simulated driving. , 2008, Accident; analysis and prevention.

[2]  M. Coles,et al.  Event-related potentials in a passive and active auditory condition: effects of diazepam and buspirone on slow wave positivity , 1997, Biological Psychology.

[3]  Alexander Strobel,et al.  Serotonergic modulation in executive functioning: Linking genetic variations to working memory performance , 2011, Neuropsychologia.

[4]  I. Craig,et al.  Expression of the dopamine transporter gene is regulated by the 3' UTR VNTR: Evidence from brain and lymphocytes using quantitative RT-PCR. , 2002, American journal of medical genetics.

[5]  G. Baal,et al.  Twin and family studies of the human electroencephalogram: a review and a meta-analysis , 2002, Biological Psychology.

[6]  E. John,et al.  Evoked-Potential Correlates of Stimulus Uncertainty , 1965, Science.

[7]  M. Kritzer,et al.  Mesostriatal and mesolimbic projections of midbrain neurons immunoreactive for estrogen receptor beta or androgen receptors in rats , 2004, The Journal of comparative neurology.

[8]  Marc Laruelle,et al.  Increased dopamine transporter availability associated with the 9-repeat allele of the SLC6A3 gene. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[9]  M. Karayiorgou,et al.  Quantitative role of COMT in dopamine clearance in the prefrontal cortex of freely moving mice , 2010, Journal of neurochemistry.

[10]  D. Pfaff,et al.  Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[11]  T. Robbins,et al.  Inhibition and the right inferior frontal cortex , 2004, Trends in Cognitive Sciences.

[12]  E. Schröger,et al.  The modulation of auditory novelty processing by working memory load in school age children and adults: a combined behavioral and event-related potential study , 2010, BMC Neuroscience.

[13]  R. Nussbaum,et al.  Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype , 2005, Nature Neuroscience.

[14]  Vince D. Calhoun,et al.  Genetic determinants of target and novelty-related event-related potentials in the auditory oddball response , 2009, NeuroImage.

[15]  R. Knight.  Decreased response to novel stimuli after prefrontal lesions in man. , 1984, Electroencephalography and clinical neurophysiology.

[16]  M. Egan,et al.  Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. , 2004, American journal of human genetics.

[17]  Pavel Jurák,et al.  Intracerebral event-related potentials to subthreshold target stimuli , 2001, Clinical Neurophysiology.

[18]  Philippe R Goldin,et al.  Neural mechanisms underlying 5-HTTLPR-related sensitivity to acute stress. , 2012, The American journal of psychiatry.

[19]  J Leon Kenemans,et al.  How Human Electrophysiology Informs Psychopharmacology: from Bottom-up Driven Processing to Top-Down Control , 2011, Neuropsychopharmacology.

[20]  Rainer Goebel,et al.  Localizing P300 Generators in Visual Target and Distractor Processing: A Combined Event-Related Potential and Functional Magnetic Resonance Imaging Study , 2004, The Journal of Neuroscience.

[21]  E. Bramon,et al.  Is there an association between the COMT gene and P300 endophenotypes? , 2006, European Psychiatry.

[22]  J. Polich.  Updating P300: An integrative theory of P3a and P3b , 2007, Clinical Neurophysiology.

[23]  B. Oranje,et al.  A single high dose of escitalopram increases mismatch negativity without affecting processing negativity or P300 amplitude in healthy volunteers , 2010, Journal of psychopharmacology.

[24]  J. L. Kenemans,et al.  Genetic polymorphisms of the dopamine and serotonin systems modulate the neurophysiological response to feedback and risk taking in healthy humans , 2012, Cognitive, Affective, & Behavioral Neuroscience.

[25]  Steven P. Hamilton,et al.  Sequence Analysis of the Serotonin Transporter and Associations with Antidepressant Response , 2005, Biological Psychiatry.

[26]  M. Fabiani,et al.  Changes in brain activity patterns in aging: the novelty oddball. , 1995, Psychophysiology.

[27]  M. Scherg,et al.  Localizing P300 Generators in Visual Target and Distractor Processing: A Combined Event-Related Potential and Functional Magnetic Resonance Imaging Study , 2004, The Journal of Neuroscience.

[28]  R. Weinshilboum,et al.  Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. , 1996, Pharmacogenetics.

[29]  A. Meyer-Lindenberg,et al.  5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression , 2005, Nature Neuroscience.

[30]  Douglas W. Jones,et al.  Genotype Influences In Vivo Dopamine Transporter Availability in Human Striatum , 2000, Neuropsychopharmacology.

[31]  A. Grace,et al.  The Catechol-O-Methyltransferase Polymorphism: Relations to the Tonic–Phasic Dopamine Hypothesis and Neuropsychiatric Phenotypes , 2004, Neuropsychopharmacology.

[32]  S. Galderisi,et al.  The cortical generators of P3a and P3b: A LORETA study , 2007, Brain Research Bulletin.

[33]  C. C. Duncan,et al.  Event-related potentials in clinical research: Guidelines for eliciting, recording, and quantifying mismatch negativity, P300, and N400 , 2009, Clinical Neurophysiology.

[34]  R. M. Murray,et al.  The Maudsley Family Study, II: Endogenous event-related potentials in familial schizophrenia , 1997, Schizophrenia Research.

[35]  B. Franke,et al.  DBH −1021C>T and COMT Val108/158Met genotype are not associated with the P300 ERP in an auditory oddball task , 2013, Clinical Neurophysiology.

[36]  P Riederer,et al.  Allelic Variation of Human Serotonin Transporter Gene Expression , 1996, Journal of neurochemistry.

[37]  Josep Marco-Pallarés,et al.  Neurophysiological markers of novelty processing are modulated by COMT and DRD4 genotypes , 2010, NeuroImage.

[38]  Andrew T. Morgan,et al.  Behavioral/systems/cognitive Striatal Dopamine D 2 /d 3 Receptors Mediate Response Inhibition and Related Activity in Frontostriatal Neural Circuitry in Humans Impulsive Behavior Is Thought to Reflect a Traitlike Characteristic That Can Have Broad Consequences for an Individual's Success and Well-be , 2022 .

[39]  I. Kondo,et al.  A 40-nucleotide repeat polymorphism in the human dopamine transporter gene , 1993, Human Genetics.

[40]  M. Timsit-Berthier,et al.  Catecholaminergic function and P300 amplitude in major depressive disorder (P300 and catecholamines). , 1995, Electroencephalography and clinical neurophysiology.

[41]  J. Mackie,et al.  What's to be done? , 1992 .

[42]  D. I. Boomsma,et al.  Genetics of the human electroencephalogram (EEG) and event-related brain potentials (ERPs): a review , 1994, Human Genetics.

[43]  David Goldman,et al.  Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. , 2006, American journal of human genetics.

[44]  J. Polich,et al.  Neuropsychology and neuropharmacology of P3a and P3b. , 2006, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[45]  P. Cowen,et al.  The effect of the serotonin transporter polymorphism (5-HTTLPR) on amygdala function: a meta-analysis , 2013, Molecular Psychiatry.

[46]  Eliza Congdon,et al.  Analysis of DRD4 and DAT polymorphisms and behavioral inhibition in healthy adults: Implications for impulsivity , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[47]  The symptomatic profile of panic disorder is shaped by the 5-HTTLPR polymorphism , 2009, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[48]  B. Glenthøj,et al.  Divergent effects of increased serotonergic activity on psychophysiological parameters of human attention. , 2008, The international journal of neuropsychopharmacology.

[49]  E. Halgren,et al.  Generators of the late cognitive potentials in auditory and visual oddball tasks. , 1998, Electroencephalography and clinical neurophysiology.

[50]  Xiufeng Xu,et al.  Association study of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism with auditory P300 in Chinese Han patients with schizophrenia , 2010, Psychiatry Research.

[51]  J. Ballenger.  The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited: Evidence of Genetic Moderation , 2012 .

[52]  Alexander Strobel,et al.  Interaction between BDNF Val66Met and Dopamine Transporter Gene Variation Influences Anxiety-Related Traits , 2007, Neuropsychopharmacology.

[53]  R. Straub,et al.  Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Iiro P. Jääskeläinen,et al.  Tryptophan Depletion Effects on EEG and MEG Responses Suggest Serotonergic Modulation of Auditory Involuntary Attention in Humans , 2002, NeuroImage.

[55]  R. Knight,et al.  Neural origins of the P300. , 2000, Critical reviews in neurobiology.

[56]  I. Ulmanen,et al.  Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. , 1995, Biochemistry.

[57]  Christian Büchel,et al.  Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter , 2005, Nature Neuroscience.

[58]  E Donchin,et al.  A new method for off-line removal of ocular artifact. , 1983, Electroencephalography and clinical neurophysiology.

[59]  Eric Stice,et al.  Frontal-Limbic White Matter Pathway Associations with the Serotonin Transporter Gene Promoter Region (5-HTTLPR) Polymorphism , 2009, The Journal of Neuroscience.

[60]  S. Fuke,et al.  The VNTR polymorphism of the human dopamine transporter (DAT1) gene affects gene expression , 2001, The Pharmacogenomics Journal.

[61]  E. Donchin,et al.  Spatiotemporal analysis of the late ERP responses to deviant stimuli. , 2001, Psychophysiology.

[62]  S. Tsai,et al.  Association analysis for dopamine D3 receptor, dopamine D4 receptor and dopamine transporter genetic polymorphisms and P300 event-related potentials for normal young females , 2003, Psychiatric genetics.

[63]  N. Freimer,et al.  5‐HTTLPR genotype and anxiety‐related personality traits: A meta‐analysis and new data , 2009, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[64]  K. Meador,et al.  Cholinergic and serotonergic effects on the P3 potential and recent memory. , 1989, Journal of clinical and experimental neuropsychology.

[65]  P. Stanzione,et al.  P300 variations in parkinsonian patients before and during dopaminergic monotherapy: a suggested dopamine component in P300. , 1991, Electroencephalography and clinical neurophysiology.

[66]  M. Caron,et al.  The dopamine transporter: A crucial component regulating dopamine transmission , 1997, Movement disorders : official journal of the Movement Disorder Society.

[67]  Robin M. Murray,et al.  Heritability and Reliability of P300, P50 and Duration Mismatch Negativity , 2006, Behavior genetics.

[68]  J. Os,et al.  Genetic association study of the P300 endophenotype in schizophrenia , 2012, Schizophrenia Research.

[69]  C. Ogura,et al.  Effect of the dopamine D2 antagonist sulpiride on event-related potentials and its relation to the law of initial value. , 1994, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[70]  R. Desimone,et al.  Multiple memory systems in the visual cortex. , 1995 .

[71]  J. Rohrbaugh,et al.  Endogenous potentials generated in the human hippocampal formation and amygdala by infrequent events. , 1980, Science.

[72]  Rainer Goebel,et al.  Attentional systems in target and distractor processing: a combined ERP and fMRI study , 2004, NeuroImage.

[73]  R. Knight.  Contribution of human hippocampal region to novelty detection , 1996, Nature.

[74]  J. O. Schenk,et al.  Characterization of Extracellular Dopamine Clearance in the Medial Prefrontal Cortex: Role of Monoamine Uptake and Monoamine Oxidase Inhibition , 2001, The Journal of Neuroscience.

[75]  Y. Kuroiwa,et al.  The correlation between P300 alterations and regional cerebral blood flow in non-demented Parkinson's disease , 2000, Neuroscience Letters.

[76]  B. Renault,et al.  Effects of Serotonin-Selective and Classical Antidepressants on the Auditory P300 Cognitive Potential , 1999, Neuropsychobiology.

[77]  T. Robbins,et al.  A componential analysis of task-switching deficits associated with lesions of left and right frontal cortex. , 2004, Brain : a journal of neurology.

[78]  K. Syndulko,et al.  Cognition in Parkinson disease: An event‐related potential perspective , 1982, Annals of neurology.

[79]  R. Stark,et al.  Functional Gene Polymorphisms in the Serotonin System and Traumatic Life Events Modulate the Neural Basis of Fear Acquisition and Extinction , 2012, PloS one.

[80]  S. Ho,et al.  Human catechol-O-methyltransferase down-regulation by estradiol , 2003, Neuropharmacology.

[81]  J. Becker,et al.  Estrous cycle-dependent variation in amphetamine-induced behaviors and striatal dopamine release assessed with microdialysis , 1989, Behavioural Brain Research.

[82]  J. Hewig,et al.  COMT Val158Met genotype and the common basis of error and conflict monitoring , 2012, Brain Research.

[83]  P. Männistö,et al.  Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. , 1999, Pharmacological reviews.

[84]  L. Pessoa.  Emotion and cognition and the amygdala: From “what is it?” to “what's to be done?” , 2010, Neuropsychologia.

[85]  Jonathan D. Cohen,et al.  Decision making, the P3, and the locus coeruleus-norepinephrine system. , 2005, Psychological bulletin.

[86]  David Goldman,et al.  Association of the G1947A COMT (Val108/158Met) gene polymorphism with prefrontal P300 during information processing , 2003, Biological Psychiatry.

[87]  Clinton D Kilts,et al.  The variable number of tandem repeats element in DAT1 regulates in vitro dopamine transporter density , 2005, BMC Genetics.

[88]  L. Pessoa.  On the relationship between emotion and cognition , 2008, Nature Reviews Neuroscience.

[89]  X Li,et al.  Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. , 1992, Genomics.