Cited by 893Neurotransmitter Receptor Influence on BehaviorPharmacogenetics and Drug MetabolismNeural and Behavioral Psychology Studies

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Catechol O -methyltransferase val 158 -met genotype and individual variation in the brain response to amphetamine

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Mattay, Venkata S., Goldberg, Terry E., Fera, Francesco, Hariri, Ahmad R., Tessitore, Alessandro, Egan, Michael F., Kolachana, Bhaskar, Callicott, Joseph H., Weinberger, Daniel R.·2003·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0931309100PMC PMC156347

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Abstract

Monamines subserve many critical roles in the brain, and monoaminergic drugs such as amphetamine have a long history in the treatment of neuropsychiatric disorders and also as a substance of abuse. The clinical effects of amphetamine are quite variable, from positive effects on mood and cognition in some individuals, to negative responses in others, perhaps related to individual variations in monaminergic function and monoamine system genes. We explored the effect of a functional polymorphism ( val 158 -met ) in the catechol O -methyltransferase gene, which has been shown to modulate prefrontal dopamine in animals and prefrontal cortical function in humans, on the modulatory actions of amphetamine on the prefrontal cortex. Amphetamine enhanced the efficiency of prefrontal cortex function assayed with functional MRI during a working memory task in subjects with the high enzyme activity val / val genotype, who presumably have relatively less prefrontal synaptic dopamine, at all levels of task difficulty. In contrast, in subjects with the low activity met / met genotype who tend to have superior baseline prefrontal function, the drug had no effect on cortical efficiency at low-to-moderate working memory load and caused deterioration at high working memory load. These data illustrate an application of functional neuroimaging in pharmacogenomics and extend basic evidence of an inverted-“U” functional-response curve to increasing dopamine signaling in the prefrontal cortex. Further, individuals with the met / met catechol O -methyltransferase genotype appear to be at increased risk for an adverse response to amphetamine.

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Authors: Mattay, V. S., Goldberg, T. E., Fera, F., Hariri, A. R., Tessitore, A., Egan, M. F., Kolachana, B., Callicott, J. H., & Weinberger, D. R.
Affiliations: National Institutes of Health (US)
ORCID: Mattay, Venkata S.
Goldberg, Terry E.
Hariri, Ahmad R.
Tessitore, Alessandro
Egan, Michael F.
Kolachana, Bhaskar
Callicott, Joseph H.
Weinberger, Daniel R.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2003-04-25
Volume: 100
Issue: 10
Pages: 6186-6191
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0931309100
PMC: PMC156347
OpenAlex: W2123636362
Cited by: 893
References: 36
Citations by year: 2026: 3 · 2025: 4 · 2024: 8 · 2023: 8 · 2022: 9 · 2021: 10 · 2020: 19 · 2019: 13 · 2018: 17 · 2017: 30 · 2016: 34 · 2015: 51 · 2014: 50 · 2013: 66 · 2012: 61
FWCI: 19.45
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Alliance for Research on Schizophrenia and Depression
National Institutes of Health
National Institute of Mental Health
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
Keywords: catechol-O-methyltransferase, COMT Val158Met polymorphism, amphetamine, prefrontal cortex, working memory, dopamine signaling, pharmacogenomics, individual differences, monoaminergic systems
MeSH terms: Brain, Catechol O-Methyltransferase, Dextroamphetamine, DNA, Genotype, Humans, Magnetic Resonance Imaging, Methionine, Organ Specificity, Valine, Amino Acid Substitution

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Catechol O -methyltransferase val 158 -met genotype and individual variation in the brain response to amphetamine

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