Cited by 769Neurotransmitter Receptor Influence on BehaviorPharmacogenetics and Drug MetabolismSchizophrenia research and treatment

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The Catechol-O-Methyltransferase Polymorphism: Relations to the Tonic–Phasic Dopamine Hypothesis and Neuropsychiatric Phenotypes

Bilder, Robert M, Volavka, Jan, Lachman, Herbert M, Grace, Anthony A·2004·Neuropsychopharmacology

DOI 10.1038/sj.npp.1300542

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Abstract

Diverse phenotypic associations with the catechol-O-methyltransferase (COMT) Val158Met polymorphism have been reported. We suggest that some of the complex effects of this polymorphism be understood from the perspective of the tonic-phasic dopamine (DA) hypothesis. We hypothesize that the COMT Met allele (associated with low enzyme activity) results in increased levels of tonic DA and reciprocal reductions in phasic DA in subcortical regions and increased D1 transmission cortically. This pattern of effects is hypothesized to yield increased stability but decreased flexibility of neural network activation states that underlie important aspects of working memory and executive functions; these effects may be beneficial or detrimental depending on the phenotype, a range of endogenous factors, and environmental exigencies. The literature on phenotypic associations of the COMT Val158Met polymorphism is reviewed, highlighting areas where this hypothesis may have explanatory value, and pointing to possible directions for refinement of relevant phenotypes and experimental evaluation of this hypothesis.

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Authors: Bilder, R. M., Volavka, J., Lachman, H. M., & Grace, A. A.
Affiliations: University of California, Los Angeles (US)
Nathan Kline Institute for Psychiatric Research (US)
Albert Einstein College of Medicine (US)
University of Pittsburgh (US)
Corresponding author: Bilder, Robert M
ORCID: Bilder, Robert M
Volavka, Jan
Lachman, Herbert M
Grace, Anthony A
Venue: Neuropsychopharmacology
Publisher: Springer Science and Business Media LLC
Published: 2004-08-11
Volume: 29
Issue: 11
Pages: 1943-1961
ISSN: 0893-133X (ISSN-L)
1740-634X
DOI: 10.1038/sj.npp.1300542
OpenAlex: W1997343027
Cited by: 769
References: 173
Citations by year: 2026: 3 · 2025: 5 · 2024: 16 · 2023: 20 · 2022: 21 · 2021: 45 · 2020: 20 · 2019: 23 · 2018: 32 · 2017: 34 · 2016: 36 · 2015: 42 · 2014: 57 · 2013: 60 · 2012: 64
FWCI: 2.35
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Neuropsychopharmacology (publishedVersion)
PubMed (publishedVersion)
Funders: National Alliance for Research on Schizophrenia and Depression
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords: catechol-O-methyltransferase, COMT Val158Met polymorphism, tonic dopamine, phasic dopamine, dopamine D1 receptor, working memory, executive function, neuropsychiatric phenotypes
MeSH terms: Animals, Mental Disorders, Catechol O-Methyltransferase, Dopamine, Humans, Phenotype, Polymorphism, Genetic

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The Catechol-O-Methyltransferase Polymorphism: Relations to the Tonic–Phasic Dopamine Hypothesis and Neuropsychiatric Phenotypes

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