Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype
Abstract
Using multimodal neuroimaging in humans, we demonstrate specific interactions between prefrontal activity and midbrain dopaminergic synthesis. A common V(108/158)M substitution in the gene for catecholamine-O-methyltransferase (COMT), an important enzyme regulating prefrontal dopamine turnover, predicted reduced dopamine synthesis in midbrain and qualitatively affected the interaction with prefrontal cortex. These data implicate a dopaminergic tuning mechanism in prefrontal cortex and suggest a systems-level mechanism for cognitive and neuropsychiatric associations with COMT.
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The inverted U-shape model of prefrontal cortical dopamine levels and function might also operate in the striatum.
“and indicates that the established inverted U-shape model of prefrontal cortical dopamine levels and function (and consequently neurocognitive performance), might also operate in the striatum.51-53”
From Striatal sensitivity during reward processing in attention-deficit/hyperactivity disorder (2012) · cites this paper as [53]
Cites
Implications of Normal Brain Development for the Pathogenesis of Schizophrenia
Weinberger, D. R. (1987) · Archives of General Psychiatry · doi:10.1001/archpsyc.1987.01800190080012 · Cited by 3,724 · see citing works
Self-citationEffect of COMT Val 108/158 Met genotype on frontal lobe function and risk for schizophrenia
Egan, M. F., Goldberg, T. E., Kolachana, B. S., Callicott, J. H., Mazzanti, C. M., Straub, R. E., Goldman, D. A., & Weinberger, D. R. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.111134598 · Cited by 2,374 · see citing works
Self-citationChen, J., Lipska, B. K., Halim, N., Ma, Q. D., Matsumoto, M., Melhem, S., Kolachana, B. S., Hyde, T. M., Herman, M. M., Apud, J., et al. (2004) · The American Journal of Human Genetics · doi:10.1086/425589 · Cited by 1,675 · see citing works
Self-citationModulation of memory fields by dopamine Dl receptors in prefrontal cortex
Williams, G. V., & Goldman-Rakic, P. S. (1995) · Nature · doi:10.1038/376572a0 · Cited by 1,593 · see citing works
The principal features and mechanisms of dopamine modulation in the prefrontal cortex
Seamans, J. K., & Yang, C. R. (2004) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2004.05.006 · Cited by 1,592 · see citing works
Mattay, V. S., Goldberg, T. E., Fera, F., Hariri, A. R., Tessitore, A., Egan, M. F., Kolachana, B., Callicott, J. H., & Weinberger, D. R. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0931309100 · Cited by 893 · see citing works
Self-citationGogos, J. A., Morgan, M., Luine, V., Santha, M., Ogawa, S., Pfaff, D., & Karayiorgou, M. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.17.9991 · Cited by 864 · see citing works
Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia
Meyer-Lindenberg, A., Miletich, R. S., Kohn, P. D., Esposito, G., Carson, R. E., Quarantelli, M., Weinberger, D. R., & Berman, K. F. (2002) · Nature Neuroscience · doi:10.1038/nn804 · Cited by 652 · see citing works
Self-citationEvidence for Abnormal Cortical Functional Connectivity During Working Memory in Schizophrenia
Meyer‐Lindenberg, A., Poline, J., Kohn, P. D., Holt, J. L., Egan, M. F., Weinberger, D. R., & Berman, K. F. (2001) · American Journal of Psychiatry · doi:10.1176/appi.ajp.158.11.1809 · Cited by 507 · see citing works
Self-citationMatsumoto, M., Weickert, C. S., Akil, M., Lipska, B. K., Hyde, T. M., Herman, M. M., Kleinman, J. E., & Weinberger, D. R. (2003) · Neuroscience · doi:10.1016/s0306-4522(02)00556-0 · Cited by 365 · see citing works
Self-citationAnatomical Substrates for Glutamate‐Dopamine Interactions
Sesack, S., Carr, D. B., Omelchenko, N., & Pinto, A. (2003) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1300.066 · Cited by 348 · see citing works
Catechol- <i>O</i> -Methyltransferase Genotype and Dopamine Regulation in the Human Brain
Akil, M., Kolachana, B. S., Rothmond, D. A., Hyde, T. M., Weinberger, D. R., & Kleinman, J. E. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-06-02008.2003 · Cited by 325 · see citing works
Self-citationCortical regulation of subcortical dopamine systems and its possible relevance to schizophrenia
Grace, A. A. (1993) · Journal of Neural Transmission · doi:10.1007/bf01245228 · Cited by 185 · see citing works
Dopa decarboxylase activity of the living human brain.
GJEDDE, A. H., Reith, J., Dyve, S., Léger, G. C., Guttman, M., Dikšić, M., Evans, A. C., & Kuwabara, H. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.7.2721 · Cited by 169 · see citing works
Differential expression of autoreceptors in the ascending dopamine systems of the human brain.
Meador‐Woodruff, J. H., Damask, S. P., & Watson, S. J. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.17.8297 · Cited by 84 · see citing works
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Friedman, N. P., & Miyake, A. (2017) · Cortex · doi:10.1016/j.cortex.2016.04.023 · Cited by 1,834 · see citing works
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Cools, R., & D'Esposito, M. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.03.028 · Cited by 1,673 · see citing works
Intermediate phenotypes and genetic mechanisms of psychiatric disorders
Meyer-Lindenberg, A., & Weinberger, D. R. (2006) · Nature reviews. Neuroscience · doi:10.1038/nrn1993 · Cited by 1,216 · see citing works
Self-citationInverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory
Vijayraghavan, S., Wang, M., Birnbaum, S. G., Williams, G. V., & Arnsten, A. F. T. (2007) · Nature Neuroscience · doi:10.1038/nn1846 · Cited by 1,013 · see citing works
Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis
Mier, D., Kirsch, P., & Meyer-Lindenberg, A. (2010) · Molecular Psychiatry · doi:10.1038/mp.2009.36 · Cited by 464 · see citing works
Self-citationForbes, E. E., Brown, S. M., Kimak, M., Ferrell, R. E., Manuck, S. B., & Hariri, A. R. (2009) · Molecular Psychiatry · doi:10.1038/sj.mp.4002086 · Cited by 408 · see citing works
Role of dopamine in the motivational and cognitive control of behavior
Cools, R. (2008) · The Neuroscientist · doi:10.1177/1073858408317009 · Cited by 352 · see citing works
Forming beliefs: Why valence matters
Sharot, T., & Garrett, N. (2016) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2015.11.002 · Cited by 345 · see citing works
Tan, H.-Y., Callicott, J. H., & Weinberger, D. R. (2007) · Cerebral Cortex · doi:10.1093/cercor/bhm069 · Cited by 266 · see citing works
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Dreher, J.-C., Meyer-Lindenberg, A., Kohn, P., & Berman, K. F. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802127105 · Cited by 230 · see citing works
Self-citationKrugel, L. K., Biele, G., Mohr, P. N. C., Li, S.-C., & Heekeren, H. R. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0905191106 · Cited by 229 · see citing works
Caspi, A., Langley, K., Milne, B., Moffitt, T. E., O’Donovan, M., Owen, M. J., Polo Tomas, M., Poulton, R., Rutter, M., Taylor, A., et al. (2008) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2007.24 · Cited by 221 · see citing works
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Schott, B. H., Seidenbecher, C. I., Fenker, D. B., Lauer, C. J., Bunzeck, N., Bernstein, H.-G., Tischmeyer, W., Gundelfinger, E. D., Heinze, H.-J., & Düzel, E. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.3463-05.2006 · Cited by 214 · see citing works
Jongkees, B. J., Hommel, B., Kühn, S., & Colzato, L. S. (2015) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2015.08.014 · Cited by 177 · see citing works
Schmahl, C., Herpertz, S. C., Bertsch, K., Ende, G., Flor, H., Kirsch, P., Lis, S., Meyer-Lindenberg, A., Rietschel, M., Schneider, M., et al. (2014) · Borderline Personality Disorder and Emotion Dysregulation · doi:10.1186/2051-6673-1-12 · Cited by 168 · see citing works
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Tan, H.-Y., Chen, Q., Goldberg, T. E., Mattay, V. S., Meyer-Lindenberg, A., Weinberger, D. R., & Callicott, J. H. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4041-07.2007 · Cited by 144 · see citing works
Self-citationImpact of interacting functional variants in COMT on regional gray matter volume in human brain
Honea, R., Verchinski, B. A., Pezawas, L., Kolachana, B. S., Callicott, J. H., Mattay, V. S., Weinberger, D. R., & Meyer-Lindenberg, A. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2008.10.064 · Cited by 128 · see citing works
Self-citationCerebellar contributions to visuomotor adaptation and motor sequence learning: an ALE meta-analysis
Bernard, J. A., & Seidler, R. D. (2013) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2013.00027 · Cited by 122 · see citing works
The Neurobiology of Thought: The Groundbreaking Discoveries of Patricia Goldman-Rakic 1937-2003
Arnsten, A. F. T. (2013) · Cerebral Cortex · doi:10.1093/cercor/bht195 · Cited by 94 · see citing works
Striatal sensitivity during reward processing in attention-deficit/hyperactivity disorder
Paloyelis, Y., Mehta, M. A., Faraone, S. V., Asherson, P., & Kuntsi, J. (2012) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2012.05.006 · Cited by 94 · see citing works
Delirium: An emerging frontier in the management of critically ill children
Smith, H. A. B., Fuchs, D. C., Pandharipande, P. P., Barr, F. E., & Ely, E. W. (2009) · Critical Care Clinics · doi:10.1016/j.ccc.2009.05.002 · Cited by 87 · see citing works
Developmental imaging genetics: Linking dopamine function to adolescent behavior
Padmanabhan, A., & Luna, B. (2014) · Brain and Cognition · doi:10.1016/j.bandc.2013.09.011 · Cited by 87 · see citing works
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van Wingen, G. A., Geuze, E., Caan, M. W. A., Kozicz, T., Olabarriaga, S. D., Denys, D., Vermetten, E., & Fernández, G. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206330109 · Cited by 77 · see citing works
Study of the Catechol‐O‐Methyltransferase (COMT) Gene with High Aggression in Children
Hirata, Y., Zai, C. C., Nowrouzi, B., Beitchman, J. H., & Kennedy, J. L. (2013) · Aggressive Behavior · doi:10.1002/ab.21448 · Cited by 65 · see citing works
Gleich, T., Deserno, L., Lorenz, R. C., Boehme, R., Pankow, A., Buchert, R., Kuhn, S., Heinz, A., Schlagenhauf, F., & Gallinat, J. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0329-15.2015 · Cited by 62 · see citing works
Michaelovsky, E., Gothelf, D., Korostishevsky, M., Frisch, A., Burg, M., Carmel, M., Steinberg, T., Inbar, D., Apter, A., & Weizman, A. (2008) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145707008085 · Cited by 53 · see citing works
Gao, S., Cheng, J., Li, G., Sun, T., Xu, Y., Wang, Y., Du, X., Xu, G., & Duan, S. (2017) · European Psychiatry · doi:10.1016/j.eurpsy.2017.03.002 · Cited by 39 · see citing works
Ray, N. J., & Strafella, A. P. (2012) · Movement Disorders · doi:10.1002/mds.25173 · Cited by 35 · see citing works
- Authors
- Meyer-Lindenberg, A., Kohn, P. D., Kolachana, B., Kippenhan, S., McInerney-Leo, A., Nussbaum, R., Weinberger, D. R., & Berman, K. F.
- Affiliations
- National Institutes of Health (US)
- Venue
- Nature Neuroscience
- Published
- 2005-04-10
- Volume
- 8
- Issue
- 5
- Pages
- 594-596
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W1993105546
- Cited by
- 428
- References
- 15
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 6 · 2023: 6 · 2022: 10 · 2021: 16 · 2020: 13 · 2019: 11 · 2018: 11 · 2017: 13 · 2016: 28 · 2015: 21 · 2014: 25 · 2013: 35 · 2012: 37
- FWCI
- 12.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- midbrain dopamine, prefrontal cortex, catechol-O-methyltransferase, COMT genotype, dopamine synthesis, gene-environment interaction, cognitive function, neuropsychiatric disorders
- MeSH terms
- Adult, Brain Mapping, Catechol O-Methyltransferase, Cognition, Dopamine, Feedback, Female, Genotype, Humans, Male, Memory, Short-Term, Mesencephalon, Metabolic Clearance Rate, Neural Pathways, Synaptic Transmission, Neuropsychological Tests, Reaction Time, Prefrontal Cortex, Amino Acid Substitution, Positron-Emission Tomography
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