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

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. +1 more·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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Crossref · 10.1073/pnas.0931309100

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  • Working memory performance in psychotic and healthy subjects relies on dopamine levels within the prefrontal cortex.

    “Studies have shown that WM performance in psychotic and healthy subjects rely on dopamine levels within the PFC (Dumontheil et al., 2011; Mattay et al., 2003; Okubo et al., 1997).”

    From Systematic reviews of the acute effects of amphetamine on working memory and other cognitive performances in healthy individuals, with a focus on the potential influence of personality traits (2023) · cites this paper as Mattay et al., 2003

    The Abstract states that prefrontal dopamine signaling is critical for working memory, and the paper reports dopamine-related differences in prefrontal function during a working-memory task in healthy volunteers. It does not establish the same relationship in psychotic subjects; the Discussion mentions schizophrenia only as a condition for which the findings may be relevant. (LLM, conf=0.87)

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  • Some human participants with lower baseline dopamine levels (Val/Val COMT) showed improved WM performance after dexamphetamine, while those with higher dopamine (met/met) showed the opposite effect.

    “some human participants who had lower baseline dopamine levels (due to Val/Val allele in COMT gene), showed improved WM performance after dexamphetamine administration, while others who had a higher dopamine level (met/met allele subjects) showed the opposite effect”

    From Systematic reviews of the acute effects of amphetamine on working memory and other cognitive performances in healthy individuals, with a focus on the potential influence of personality traits (2023) · cites this paper as Mattay et al., 2003

    The Results report faster working-memory reaction times after amphetamine in val/val participants, with no change in accuracy. Met/met participants showed worse accuracy and slower reaction times only at the highest working-memory load; the claim omits that condition. The paper describes the groups’ relative baseline dopamine levels as presumed, rather than measured. (LLM, conf=0.87)

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  • Methionine substitutions in COMT increase the stress response in mice and make humans more susceptible to cognitive impairment following stress and psychostimulant medication.

    “For example, methionine substitutions in COMT increase the stress response in mice75 and make humans more susceptible to cognitive impairment following stress and psychostimulant medication74.”

    From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [74]

    The Results report that amphetamine worsened cognitive performance in humans with the met/met COMT genotype, and the Abstract specifies deterioration at high working-memory load. This supports the psychostimulant part of the claim, but our copy does not establish susceptibility to cognitive impairment following stress. The mouse claim is attached to a different citation, not this source. (LLM, conf=0.88)

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  • The methionine substitution in COMT reduces the ability of COMT to catabolize dopamine and increases vulnerability to stress- or stimulant-induced working memory impairments in human subjects and mice.

    “the methionine substitution in the COMT protein that results from one of the COMT polymorphisms reduces the ability of COMT to catabolize dopamine and increases vulnerability to stress- or stimulant-induced working memory impairments in human subjects74 and in mice75.”

    From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [74]

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Cites

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Research works printed but not linked: 2

  1. [18]Mannisto P, Kaakkola S. Pharmacol Rev. 1999;51:593–628. [PubMed] [Google Scholar]
  2. [25]Floresco S, Phillips A. Behav Neurosci. 2001;115:934–939. [PubMed] [Google Scholar]

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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
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
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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