Functional Variation of the Dopamine D2 Receptor Gene Is Associated with Emotional Control as well as Brain Activity and Connectivity during Emotion Processing in Humans

Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D2 receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D2 receptor gene (DRD2) (rs1076560, guanine > thymine or G > T) shifts splicing of the two protein isoforms (D2 short, mainly presynaptic, and D2 long) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced “emotion control” compared with GT subjects. Functional magnetic resonance imaging in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D2 signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs.

[1]  Mark H Lewis,et al.  D2-Like Dopamine Receptor Mediation of Social-Emotional Reactivity in a Mouse Model of Anxiety: Strain and Experience Effects , 1998, Neuropsychopharmacology.

[2]  G. Glover,et al.  Reflecting upon Feelings: An fMRI Study of Neural Systems Supporting the Attribution of Emotion to Self and Other , 2004, Journal of Cognitive Neuroscience.

[3]  J. Feldon,et al.  Mesolimbic dopaminergic pathways in fear conditioning , 2004, Progress in Neurobiology.

[4]  W. Sadee,et al.  Single nucleotide polymorphism genotyping using allele-specific PCR and fluorescence melting curves. , 2003, BioTechniques.

[5]  R. Dolan,et al.  Emotion, Cognition, and Behavior , 2002, Science.

[6]  M. Bucan,et al.  Emotional response in dopamine D2L receptor-deficient mice , 2008, Behavioural Brain Research.

[7]  S. Cichon,et al.  Neural Mechanisms of a Genome-Wide Supported Psychosis Variant , 2009, Science.

[8]  Danielle S. Bassett,et al.  A validated network of effective amygdala connectivity , 2007, NeuroImage.

[9]  Daniel R. Weinberger,et al.  Variation of Human Amygdala Response During Threatening Stimuli as a Function of 5′HTTLPR Genotype and Personality Style , 2005, Biological Psychiatry.

[10]  Joseph E LeDoux Fear and the brain: where have we been, and where are we going? , 1998, Biological Psychiatry.

[11]  M. Egan,et al.  Effect of Catechol-O-Methyltransferase val158met Genotype on Attentional Control , 2005, The Journal of Neuroscience.

[12]  E. Kandel,et al.  Transient Overexpression of Striatal D2 Receptors Impairs Operant Motivation and Interval Timing , 2007, The Journal of Neuroscience.

[13]  J. Tanaka,et al.  The NimStim set of facial expressions: Judgments from untrained research participants , 2009, Psychiatry Research.

[14]  Giuseppe Blasi,et al.  Neural mechanisms of genetic risk for impulsivity and violence in humans. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Andreas Meyer-Lindenberg,et al.  Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation. , 2006, Archives of general psychiatry.

[16]  J. Gross,et al.  The cognitive control of emotion , 2005, Trends in Cognitive Sciences.

[17]  Larry Kokkinidis,et al.  Inhibition of amygdaloid dopamine D2 receptors impairs emotional learning measured with fear-potentiated startle , 2001, Brain Research.

[18]  P. Costa,et al.  Validation of the five-factor model of personality across instruments and observers. , 1987, Journal of personality and social psychology.

[19]  E. Borrelli,et al.  Genetically Determined Interaction between the Dopamine Transporter and the D2 Receptor on Prefronto-Striatal Activity and Volume in Humans , 2009, The Journal of Neuroscience.

[20]  R. C. Oldfield The assessment and analysis of handedness: the Edinburgh inventory. , 1971, Neuropsychologia.

[21]  Leonardo Fazio,et al.  Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory , 2007, Proceedings of the National Academy of Sciences.

[22]  P. Vernon,et al.  Heritability of the big five personality dimensions and their facets: a twin study. , 1996, Journal of personality.

[23]  J. Callicott,et al.  Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. , 2004, The American journal of psychiatry.

[24]  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.

[25]  Murray B Stein,et al.  COMT Polymorphisms and Anxiety-Related Personality Traits , 2005, Neuropsychopharmacology.

[26]  J. Seamans,et al.  The principal features and mechanisms of dopamine modulation in the prefrontal cortex , 2004, Progress in Neurobiology.

[27]  J. Mazziotta,et al.  Modulating emotional responses: effects of a neocortical network on the limbic system , 2000, Neuroreport.

[28]  R. McCrae,et al.  Heritability of facet-level traits in a cross-cultural twin sample: support for a hierarchical model of personality. , 1998, Journal of personality and social psychology.

[29]  David Goldman,et al.  Genetic origins of anxiety in women: a role for a functional catechol-O-methyltransferase polymorphism , 2003, Psychiatric genetics.

[30]  Leonardo Fazio,et al.  Activity in medial prefrontal cortex during cognitive evaluation of threatening stimuli as a function of personality style , 2007, Brain Research Bulletin.

[31]  Andreas Heinz,et al.  Catechol-O-Methyltransferase val158met Genotype Affects Processing of Emotional Stimuli in the Amygdala and Prefrontal Cortex , 2005, The Journal of Neuroscience.

[32]  The effects of intra-amygdaloid infusions of a D2 dopamine receptor antagonist on Pavlovian fear conditioning. , 2000, Behavioral neuroscience.

[33]  Henry Kranzler,et al.  Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African- and European-American and Japanese populations and in alcohol-dependent subjects , 1997, Human Genetics.

[34]  R. C. Hall,et al.  Amphetamine psychosis: clinical presentations and differential diagnosis. , 1988, Psychiatric medicine.

[35]  L. Vanderschuren,et al.  Critical Involvement of Dopaminergic Neurotransmission in Impulsive Decision Making , 2006, Biological Psychiatry.

[36]  Leonardo Fazio,et al.  Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia. , 2009, Brain : a journal of neurology.

[37]  C. Barbaranelli,et al.  The "big five questionnaire": A new questionnaire to assess the five factor model , 1993 .

[38]  K. Lesch Alcohol dependence and gene x environment interaction in emotion regulation: Is serotonin the link? , 2005, European journal of pharmacology.

[39]  S. Rauch,et al.  Neurobiology of emotion perception I: the neural basis of normal emotion perception , 2003, Biological Psychiatry.

[40]  Alessandro Usiello,et al.  Distinct functions of the two isoforms of dopamine D2 receptors , 2000, Nature.

[41]  D. Goldman,et al.  A Non-Additive Interaction of a Functional MAO-A VNTR and Testosterone Predicts Antisocial Behavior , 2008, Neuropsychopharmacology.

[42]  Kevin N. Ochsner,et al.  For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion , 2004, NeuroImage.

[43]  A. Grace,et al.  Dopamine Attenuates Prefrontal Cortical Suppression of Sensory Inputs to the Basolateral Amygdala of Rats , 2001, The Journal of Neuroscience.

[44]  A. Arnsten,et al.  Neurobiology of Executive Functions: Catecholamine Influences on Prefrontal Cortical Functions , 2004, Biological Psychiatry.

[45]  G. Shulman,et al.  Medial prefrontal cortex and self-referential mental activity: Relation to a default mode of brain function , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Christopher J Rennie,et al.  Mode of Functional Connectivity in Amygdala Pathways Dissociates Level of Awareness for Signals of Fear , 2006, The Journal of Neuroscience.

[47]  Christian Montag,et al.  The BDNF Val66Met polymorphism affects amygdala activity in response to emotional stimuli: Evidence from a genetic imaging study , 2008, NeuroImage.

[48]  Andreas Meyer-Lindenberg,et al.  Neural connectivity as an intermediate phenotype: Brain networks under genetic control , 2009, Human brain mapping.

[49]  F. Guarraci,et al.  The effects of intra-amygdaloid infusions of a D2 dopamine receptor antagonist on Pavlovian fear conditioning. , 2000, Behavioral neuroscience.

[50]  O. Blin,et al.  Dopaminergic Contribution to the Regulation of Emotional Perception , 2005, Clinical neuropharmacology.

[51]  Philip K. McGuire,et al.  Opposite Effects of Catechol-O-Methyltransferase Val158Met on Cortical Function in Healthy Subjects and Patients with Schizophrenia , 2009, Biological Psychiatry.

[52]  B. Yu,et al.  Catechol O-methyltransferase genetic polymorphism in panic disorder. , 2002, The American journal of psychiatry.

[53]  D L Price,et al.  Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies. , 1993, Proceedings of the National Academy of Sciences of the United States of America.