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Variations in the Catechol O-methyltransferase Polymorphism and Prefrontally Guided Behaviors in Adolescents

  • Dustin Wahlstrom
    Correspondence
    Address reprint requests to Dustin Wahlstrom, B.A., Department of Psychology, 75 East River Rd., University of Minnesota, Minneapolis, MN 55455
    Affiliations
    Department of Psychology, University of Minnesota—Twin Cities, Minneapolis, Minnesota

    Center for Neurobehavioral Development, University of Minnesota—Twin Cities, Minneapolis, Minnesota
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  • Tonya White
    Affiliations
    Center for Neurobehavioral Development, University of Minnesota—Twin Cities, Minneapolis, Minnesota

    Department of Psychiatry, University of Minnesota—Twin Cities, Minneapolis, Minnesota
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  • Catalina J. Hooper
    Affiliations
    Department of Psychology, University of Minnesota—Twin Cities, Minneapolis, Minnesota

    Center for Neurobehavioral Development, University of Minnesota—Twin Cities, Minneapolis, Minnesota
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  • Suzanne Vrshek-Schallhorn
    Affiliations
    Department of Psychology, University of Minnesota—Twin Cities, Minneapolis, Minnesota
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  • William S. Oetting
    Affiliations
    Department of Medicine—Genetics, University of Minnesota—Twin Cities, Minneapolis, Minnesota

    Institute of Human Genetics, University of Minnesota—Twin Cities, Minneapolis, Minnesota.
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  • Marcia J. Brott
    Affiliations
    Department of Medicine—Genetics, University of Minnesota—Twin Cities, Minneapolis, Minnesota

    Institute of Human Genetics, University of Minnesota—Twin Cities, Minneapolis, Minnesota.
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  • Monica Luciana
    Affiliations
    Department of Psychology, University of Minnesota—Twin Cities, Minneapolis, Minnesota

    Center for Neurobehavioral Development, University of Minnesota—Twin Cities, Minneapolis, Minnesota
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      Background

      The catechol-O-methyltransferase (COMT) gene codes for an enzyme that degrades prefrontal cortex (PFC) synaptic dopamine. Of two identified alleles (Met and Val), the Met allele results in COMT activity that is up to 4 times less pronounced than that conferred by the Val allele, resulting in greater PFC dopamine concentrations. Met-Met homozygotes perform better than individuals who possess the Val allele on PFC-mediated cognitive tasks. These genotypic variations and their associations with executive functions have been described in adults and prepubescent children, but there is a paucity of research assessing these relations in adolescent samples.

      Methods

      In this study, 70 children aged 9–17 were genotyped for COMT and completed measures of working memory, attention, fine motor coordination, and motor speed.

      Results

      COMT genotype modulated all but the motor speed measures. The Val-Met genotype was optimal for performance in this adolescent sample.

      Conclusions

      Results are discussed within the context of developmental changes in the dopaminergic system during adolescence.

      Key Words

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      References

        • Abi-Dargham A.
        • Mawlawi O.
        • Lombardo I.
        • Gil R.
        • Martinez D.
        • Huang Y.
        • et al.
        Prefrontal dopamine D1 receptors and working memory in schizophrenia.
        J Neurosci. 2002; 22: 3708-3719
        • Adriani W.
        • Chiarotti F.
        • Laviola G.
        Elevated novelty seeking and peculiar d-amphetamine sensitization in periadolescent mice compared with adult mice.
        Behav Neurosci. 1998; 112: 1152-1166
        • Andersen S.L.
        • Dumont N.L.
        • Teicher M.H.
        Developmental differences in dopamine synthesis inhibition by (+/−)-7-OH-DPAT.
        Naunyn Schmiedebergs Arch Pharmacol. 1997; 356: 173-181
        • Banken J.A.
        Clinical utility of considering digits forward and digits backward as separate components of the Wechsler Adult Intelligence Scale-Revised.
        J Clin Psychol. 1985; 41: 686-691
        • Bellgrove M.A.
        • Domschke K.
        • Hawi Z.
        • Kirley A.
        • Mullins C.
        • Robertson I.H.
        • et al.
        The methionine allele of the COMT polymorphism impairs prefrontal cognition in children and adolescents with ADHD.
        Exp Brain Res. 2005 (Available: http://www.springerlink.com/media/MFTA2GMGWG 7QF0GUUBEX/Contributions/M/F/7/E/MF7ELW7ME7699THB_html/fulltext.html (accessed June 6, 2005))
        • Coulter C.L.
        • Happe H.K.
        • Murrin L.C.
        Postnatal development of the dopamine transporter: A quantitative autoradiographic study.
        Dev Brain Res. 1996; 92: 172-181
        • Diamond A.
        • Briand L.
        • Fossella J.
        • Gehlbach L.
        Genetic and neurochemical modulation of prefrontal cognitive functions in children.
        Am J Psychiatry. 2004; 161: 125-132
        • Egan M.F.
        • Goldberg T.E.
        • Kolachana B.S.
        • Callicott J.H.
        • Mazzanti C.M.
        • Straub R.E.
        • et al.
        Effect of COMT Val108/158Met genotype on frontal lobe function and risk for schizophrenia.
        Proc Natl Acad Sci of U S A. 2001; 98: 6917-6922
        • Glatt S.J.
        • Faraone S.V.
        • Tsuang M.T.
        Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: Meta-analysis of case−control and family-based studies.
        Am J Psychiatry. 2003; 160: 469-476
        • Glickstein S.B.
        • DeSteno D.A.
        • Hof P.R.
        • Schmauss C.
        Mice lacking dopamine D2 and D3 receptors exhibit differential activation of prefrontal cortical neurons during tasks requiring attention.
        Cereb Cortex. 2005; 15: 1016-1024
        • Gogos J.
        • Morgan M.
        • Luine V.
        • Santha M.
        • Ogawa S.
        • Pfaff D.
        • Karayiorgou M.
        Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior.
        Proc Natl Acad Sci U S A. 1998; 95: 9991-9996
        • Goldberg T.E.
        • Egan M.F.
        • Gscheidle T.
        • Coppola R.
        • Weickert T.
        • Kolachana B.S.
        • et al.
        Executive subprocesses in working memory: Relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia.
        Arch Gen Psychiatry. 2003; 60: 889-896
        • Goldman-Rakic P.S.
        The cortical dopamine system: Role in memory and cognition.
        Adv Pharmacol. 1998; 42: 707-711
        • Goldman-Rakic P.S.
        • Brown R.M.
        Regional changes in monoamines in cerebral cortex and subcortical structures of aging rhesus monkeys.
        Neuroscience. 1981; 6: 177-187
        • Granon S.
        • Passetti F.
        • Thomas K.L.
        • Dalley J.W.
        • Everitt B.J.
        • Robbins T.W.
        Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex.
        J Neurosci. 2000; 20: 1208-1215
        • Grossman M.H.
        • Emanuel B.S.
        • Budaf M.L.
        Chromosomal mapping of the human catechol O-methyltransferase gene to 22q11.1-q11.2.
        Genomics. 1992; 12: 822-825
        • Halstead W.C.
        Brain and Intelligence. University of Chicago Press, Chicago1947
        • Huotari M.
        • Gogos J.
        • Karayiorgou M.
        • Koponen O.
        • Forsberg M.
        • Raasmaja A.
        • et al.
        Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice.
        Eur J Neurosci. 2002; 15: 246-256
        • Kalsbeek A.
        • Voorn P.
        • Buijs R.M.
        • Pool C.W.
        • Uylings H.B.M.
        Development of the dopaminergic innervation in the prefrontal cortex of the rat.
        J Comp Neurol. 1998; 269: 58-72
        • Kaufman A.S.
        • McLean J.
        • Reynolds C.
        Analysis of WAIS-R factor patterns by sex and race.
        J Clin Psychol. 1991; 47: 548-557
        • Lachman H.M.
        • Papolos D.F.
        • Saito T.
        • Yu Y.M.
        • Szumlanski C.
        • Weinshilboum R.
        Human catechol O-methyltransferase pharmacogenetics: Description of a functional polymorphism and its potential application to neuropsychiatric disorders.
        Pharmacogenetics. 1996; 6: 243-250
        • Laviola G.
        • Wood R.G.
        • Kuhn C.
        • Francis R.L.P.
        Cocaine sensitization in preiadolescent and adult rats.
        J Psychopharmacol Exp Ther. 1995; 275: 345-357
        • Leslie C.A.
        • Robertson M.W.
        • Cutler A.J.
        • Bennett Jr, J.P.
        Postnatal development of D1 dopamine receptors in the medial prefrontal cortex, striatum and nucleus accumbens of normal and neonatal 6-hydroxydopamine treated rats: A quantitative autoradiographic analysis.
        Dev Brain Res. 1991; 62: 109-114
        • Lezak M.D.
        • Howieson D.B.
        • Loring D.W.
        Neuropsychological Assessment. 4th ed. Oxford University Press, New York2004
        • Lotta T.
        • Vidgren J.
        • Tilgmann C.
        • Ulmanen I.
        • Melén K.
        • Julkunen I.
        • Taskinen J.
        Kinetics of human soluble and membrane-bound catechol O-methyltransferase: A revised mechanism and description of the thermolabile variant of the enzyme.
        Biochemistry. 1995; 34: 4202-4210
        • Luciana M.
        • Collins P.F.
        Dopaminergic modulation of working memory for spatial but not object cues in normal humans.
        J Cog Neurosci. 1997; 9: 330-347
        • Luciana M.
        • Depue R.A.
        • Arbisi P.
        • Leon A.
        Facilitation of working memory in humans by a D2 dopamine receptor agonist.
        J Cog Neurosci. 1992; 4: 58-68
        • Luciana M.
        • Hanson K.L.
        • Whitley C.B.
        A preliminary report on dopamine system reactivity in PKU: Acute effects of haloperidol on neuropsychological, physiological, and neuroendocrine functions.
        Psychopharmacology. 2004; 175: 18-25
        • Malhotra A.K.
        • Kestler L.J.
        • Mazzanti C.
        • Bates J.A.
        • Goldberg T.
        • Goldman D.
        A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition.
        Am J Psychiatry. 2002; 159: 652-654
        • Mattay V.S.
        • Goldberg T.E.
        • Fera F.
        • Hariri A.R.
        • Tessitore A.
        • Egan M.F.
        • et al.
        Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine.
        Proc Natl Acad Sci U S A. 2003; 100: 6186-6191
        • Marshall W.A.
        • Tanner J.M.
        Variations in pattern of pubertal changes in girls.
        Arch Dis Child. 1969; 44: 291-303
        • Marshall W.A.
        • Tanner J.M.
        Variations in pattern of pubertal changes in boys.
        Arch Dis Child. 1970; 45: 13-23
        • Mills S.
        • Langley K.
        • Van den Bree M.
        • Street E.
        • Turic D.
        • Owen M.J.
        • et al.
        No evidence of association between Catechol-O-Methyltransferase (COMT) Val158Met genotype and performance on neuropsychological tasks in children with ADHD: A case-control study.
        BMC Psychiatry. 2004; 4: 15-19
        • Monchi O.
        • Petrides M.
        • Doyon J.
        • Postuma R.B.
        • Worsley K.
        • Dagher A.
        Neural bases of set-shifting deficits in Parkinson’s disease.
        J Neurosci. 2004; 24: 702-710
        • Munafo M.R.
        • Bowes L.
        • Clark T.G.
        • Flint J.
        Lack of association of the COMT (Val(158/108) Met) gene and schizophrenia: A meta-analysis of case-control studies.
        Mol Psychiatry. 2005 (Available: http://www.nature.com/cgitaf/DynaPage.taf?file=/mp/journal/vaop/ncurrent/full/4001664a.html&filetype=pdf (accessed June 6, 2005))
        • Moron J.A.
        • Brockington A.
        • Wise R.A.
        • Rocha B.A.
        • Hope B.T.
        Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: Evidence from knock-out mouse lines.
        J Neurosci. 2002; 22: 389-395
        • Napolitano A.
        • Cesura A.M.
        • Da Prada M.
        The role of monoamine oxidase and catechol O-methyltransferase in dopaminergic neurotransmission.
        J Neural Transm. 1995; 45: 35-45
        • Oldfield R.C.
        The assessment and analysis of handedness: The Edinburgh Inventory.
        Neuropsychologia. 1971; 9: 97-113
        • Rosa A.
        • Peralta V.
        • Cuesta M.J.
        • Zarzuela A.
        • Serrano F.
        • Martinez-Larrea A.
        • Fananas L.
        New evidence of association between COMT gene and prefrontal neurocognitive function in healthy individuals from sibling pairs discordant for psychosis.
        Am J Psychiatry. 2004; 161: 1110-1112
        • Rosenberg D.R.
        • Lewis D.A.
        Changes in the dopaminergic innervation of monkey prefrontal cortex during late postnatal development: A tyrosine hydroxylase immunohistochemical study.
        Biol Psychiatry. 1994; 36: 272-277
        • Rosenberg D.R.
        • Lewis D.A.
        Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: A tyrosine hydroxylase immunohistochemical analysis.
        J Comp Neurol. 1995; 358: 383-400
        • Roy E.A.
        • Square-Storer P.A.
        Evidence for common expressions of apraxia.
        in: Hammond G.R. Cerebral Control of Speech and Limb Movements. North-Holland, Amsterdam1990: 477-502
        • Sawaguchi T.
        • Goldman-Rakic P.S.
        D1 dopamine receptors in prefrontal cortex: Involvement in working memory.
        Science. 1991; 251: 947-950
        • Seeman P.
        • Bzowej N.H.
        • Guan H.C.
        • Bergeron C.
        • Becker L.E.
        • Reynolds G.P.
        • et al.
        Human brain dopamine receptors in children and aging adults.
        Synapse. 1987; 1: 399-404
        • Servan-Schreiber D.
        • Carter C.S.
        • Bruno R.M.
        • Cohen J.D.
        Dopamine and the mechanisms of cognition: Part II.
        Biol Psychiatry. 1998; 43: 723-729
        • Sesak S.R.
        • Hawrylak V.A.
        • Matus C.
        • Guido M.A.
        • Levey A.I.
        Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter.
        J Neurosci. 1998; 18: 2697-2708
        • Spear L.P.
        • Brake S.C.
        Periadolescence: Age-dependent behavior and psychopharmacological responsivity in rats.
        Dev Psychobiol. 1983; 16: 83-109
        • Tarazi F.I.
        • Tomasini E.C.
        • Baldessarini R.J.
        Postnatal development of dopamine D1-like receptors in rat cortical and striatolimbic brain regions: An autoradiographic study.
        Dev Neurosci. 1999; 21: 43-49
        • Teicher M.H.
        • Barber N.I.
        • Gelbard H.A.
        • Gallitano A.L.
        • Campbell A.
        • Marsh E.
        • Baldessarini R.J.
        Developmental differences in acute nigrostriatal and mesocorticolimbic system response to haloperidol.
        Neuropsychopharmacology. 1993; 9: 147-156
        • Tunbridge E.M.
        • Bannerman D.M.
        • Sharp T.
        • Harrison P.J.
        COMT inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex.
        J Neurosci. 2004; 24: 5331-5335
        • Wang Y.
        • Chan G.L.Y.
        • Holden J.E.
        • Dobko T.
        • Mak E.
        • Schulzer M.
        • et al.
        Age-dependent decline of dopamine D1 receptors in human brain: A PET study.
        Synapse. 1998; 30: 56-61
        • Volkow N.D.
        • Gur R.C.
        • Wang G.J.
        • Fowler J.S.
        • Moberg P.J.
        • Ding Y.S.
        • et al.
        Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals.
        Am J Psychiatry. 1998; 155: 344-349
        • Wechsler D.
        Wechsler Intelligence Scale for Children—Third Edition. Psychological Corporation, San Antonio, TX1991
        • Wechsler D.
        Wechsler Adult Intelligence Scale—Third Edition. Psychological Corporation, San Antonio, TX1997
        • Wechsler D.
        Wechsler Memory Scale—Third Edition. Psychological Corporation, San Antonio, TX1997
        • Weinshilboum R.M.
        • Otterness D.M.
        • Szumlanski C.L.
        Methylation pharmacogenetics: Catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase.
        Annu Rev Pharmacol Toxicol. 1999; 39: 19-52
        • Weinshilboum R.M.
        • Raymond F.A.
        Inheritance of low erythrocyte catechol-o-methyltransferase activity in man.
        Am J Hum Genet. 1977; 29: 125-135
        • Williams G.V.
        • Goldman-Rakic P.S.
        Modulation of memory fields by dopamine D1 receptors in prefrontal cortex.
        Nature. 1995; 376: 572-575
        • Yang Y.K.
        • Chiu N.T.
        • Chen C.C.
        • Chen M.
        • Yeh T.L.
        • Lee I.H.
        Correlation between fine motor activity and striatal dopamine D2 receptor density in patients with schizophrenia and healthy controls.
        Psychiatry Res Neuroimaging. 2003; 123: 191-197
        • Yang Y.K.
        • Yeh T.L.
        • Chiu N.T.
        • Lee I.H.
        • Chen P.S.
        • Lee L.
        • Jeffries K.J.
        Association between cognitive performance and striatal dopamine binding is higher in timing and motor tasks in patients with schizophrenia.
        Psychiatry Res Neuroimaging. 2004; 131: 209-216