title: DRD2 polymorphisms modulate reward and emotion processing, dopamine neurotransmission and openness to experience.
abstract: Dopamine (DA) neurotransmission through D2 receptors (DRD2) has been implicated in the regulation of reward processing, cognition and the effects of drugs of abuse, and also has significant effects in responses to stressors and salient aversive stimuli. An examination of the influence of genetic variation across multiple psychophysical measures therefore appears critical to understand the neurobiology of DA-modulated complex personality traits and psychiatric illnesses. To examine inter-individual variation in the function of DRD2 modulated mechanisms in healthy humans, we used a haplotype-based and single nucleotide polymorphism (SNP) investigation. Their effects were interrogated with functional magnetic resonance imaging during reward and emotional processing. We found that a haplotype block composed by two SNPs, rs4274224 and rs4581480, affected the hemodynamic responses of the dorsolateral prefrontal cortex (DLPFC) during reward expectation and the subgenual anterior cingulate cortices (sgACC) during implicit emotional processing. Exploratory analysis within the significant haplotype block revealed the same functional effects only for the SNP rs4274224. Further analysis on rs4274224 using functional connectivity and positron emission tomography (PET) measures of DA D2/3 receptor mediated neurotransmission confirmed a gene effect on the functional connectivity of the DLPFC during reward anticipation and subcortical stress induced DA release. At a phenotypic trait level, significant effects of genotype were obtained for the NEO PI-R "Openness to Experience" and further correlated with neuroimaging data. Overall, these results show significant neurobiological effects of genotype variation in DRD2 on multiple functional domains, such as emotional, stress and reward processing. As such, it contributes to normal variation and potentially to vulnerability to psychopathology associated with those functions, such as risk for mood and substance use disorders.
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Peciña
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Mickey
authors.forename: Tiffany
authors.initials: T
authors.lastname: Love
authors.forename: Heng
authors.initials: H
authors.lastname: Wang
authors.forename: Scott A
authors.initials: SA
authors.lastname: Langenecker
authors.forename: Colin
authors.initials: C
authors.lastname: Hodgkinson
authors.forename: Pei-Hong
authors.initials: PH
authors.lastname: Shen
authors.forename: Sandra
authors.initials: S
authors.lastname: Villafuerte
authors.forename: David
authors.initials: D
authors.lastname: Hsu
authors.forename: Sara L
authors.initials: SL
authors.lastname: Weisenbach
authors.forename: Christian S
authors.initials: CS
authors.lastname: Stohler
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.forename: Jon-Kar
authors.initials: JK
authors.lastname: Zubieta
mesh_terms: D000328:Adult; D004298:Dopamine / Q000378:metabolism*; D004644:Emotions / Q000502:physiology*; D005260:Female; D059907:Functional Neuroimaging; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010551:Personality / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D012201:Reward; D009435:Synaptic Transmission / Q000235:genetics*
chemical_list: D017448:Receptors, Dopamine D2; D004298:Dopamine