Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation

Emily M. Drabant, Ahmad R. Hariri, Andreas Meyer-Lindenberg, Karen E. Munoz, Venkata S. Mattay, Bhaskar S. Kolachana, Michael F. Egan, Daniel R. Weinberger

Research output: Contribution to journalArticlepeer-review

Abstract

Context: Catechol O-methyltransferase (COMT), the major enzyme determining cortical dopamine flux, has a common functional polymorphism (val 158met) that affects prefrontal function and working memory capacity and has also been associated with anxiety and emotional dysregulation. Objectives: To examine COMT val158met 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. Design: Within-subject functional magnetic resonance imaging study. Setting: 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.

Original languageEnglish (US)
Pages (from-to)1396-1406
Number of pages11
JournalArchives of general psychiatry
Volume63
Issue number12
DOIs
StatePublished - Dec 2006

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Psychiatry and Mental health

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