title: Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation.
abstract: BACKGROUND
  Catechol O-methyltransferase (COMT), the major enzyme determining cortical dopamine flux, has a common functional polymorphism (val(158)met) that affects prefrontal function and working memory capacity and has also been associated with anxiety and emotional dysregulation.
  
  
  OBJECTIVE
  To examine COMT val(158)met effects on corticolimbic circuitry reactivity and functional connectivity during processing of biologically salient stimuli, as well as the relationship to the temperamental trait of novelty seeking.
  
  
  METHODS
  Within-subject functional magnetic resonance imaging study.
  
  
  METHODS
  National Institute of Mental Health, Genes, Cognition, and Psychosis Program, Bethesda, Md. Patients One hundred one healthy subjects of both sexes.
  
  
  RESULTS
  We found that the met allele was associated with a dose-dependent increase in hippocampal formation and ventrolateral prefrontal cortex activation during viewing of faces displaying negative emotion. In met/met homozygotes, limbic and prefrontal regions showed increased functional coupling. Moreover, in these same subjects, the magnitude of amygdala-orbitofrontal coupling was inversely correlated with novelty seeking, an index of temperamental inflexibility.
  
  
  CONCLUSIONS
  Our results indicate that heritable variation in dopamine neurotransmission associated with the met allele of the COMT polymorphism results in heightened reactivity and connectivity in corticolimbic circuits. This may reflect a genetic predisposition for inflexible processing of affective stimuli, a mechanism possibly accounting for aspects of arousal and behavioral control that contribute to emotional dysregulation previously reported in met/met individuals.
authors.affiliation: Genes, Cognition, and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health/DHHS, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Drabant
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Hariri
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.forename: Karen E
authors.initials: KE
authors.lastname: Munoz
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Mattay
authors.forename: Bhaskar S
authors.initials: BS
authors.lastname: Kolachana
authors.forename: Michael F
authors.initials: MF
authors.lastname: Egan
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
mesh_terms: D000328:Adult; D000339:Affect / Q000502:physiology* / Q000528:radiation effects*; D000342:Affective Symptoms / Q000175:diagnosis / Q000235:genetics*; D000679:Amygdala / Q000502:physiology; D001143:Arousal / Q000235:genetics / Q000502:physiology*; D001931:Brain Mapping / Q000379:methods; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005106:Exploratory Behavior / Q000502:physiology; D005149:Facial Expression; D005260:Female; D005838:Genotype; D006801:Humans; D008032:Limbic System / Q000502:physiology*; D008279:Magnetic Resonance Imaging / Q000706:statistics & numerical data; D008297:Male; D008715:Methionine / Q000235:genetics; D009434:Neural Pathways / Q000502:physiology; D010100:Oxygen / Q000097:blood; D011110:Polymorphism, Genetic / Q000502:physiology*; D017397:Prefrontal Cortex / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology; D013694:Temperament / Q000502:physiology; D014633:Valine / Q000235:genetics; D014796:Visual Perception / Q000502:physiology
chemical_list: D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine; D010100:Oxygen