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Catechol O -methyltransferase val 158 -met genotype and individual variation in the brain response to amphetamine
Open accessAbstract
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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“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
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“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
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“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]
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“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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Effect of COMT Val 108/158 Met genotype on frontal lobe function and risk for schizophrenia
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Stress signalling pathways that impair prefrontal cortex structure and function
Arnsten, A. F. T. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2648 · Cited by 3,299
Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence
Harrison, P. J., & Weinberger, D. R. (2005) · Molecular Psychiatry · doi:10.1038/sj.mp.4001558 · Cited by 2,020
Self-citationInhibition and impulsivity: behavioral and neural basis of response control
Bari, A., & Robbins, T. W. (2013) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.06.005 · Cited by 1,921
Inverted-U–Shaped Dopamine Actions on Human Working Memory and Cognitive Control
Cools, R., & D'Esposito, M. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.03.028 · Cited by 1,673
The activation of attentional networks
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Metadata
- 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
- 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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