Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

COMT genotype predicts cortical-limbic D1 receptor availability measured with [11C]NNC112 and PET

Molecular Psychiatry volume 13, pages 821–827 (2008)Cite this article

Abstract

A common polymorphism (val158met) in the gene encoding catechol-O-methyltransferase (COMT) has been shown to affect dopamine (DA) tone in cortex and cortical functioning. D1 receptors are the main DA receptors in the cortex, and studies have shown that decreased levels of cortical DA are associated with upregulation of D1 receptor availability, as measured with the positron-emission tomography (PET) radiotracer [11C]NNC112. We compared [11C]NNC 112 binding in healthy volunteers homozygous for the Val allele compared with Met carriers. Subjects were otherwise matched for parameters known to affect [11C]NNC 112 binding. Subjects with Val/Val alleles had significantly higher cortical [11C]NNC 112 binding compared with Met carriers, but did not differ in striatal binding. These results confirm the prominent role of COMT in regulating DA transmission in cortex but not striatum, and the reliability of [11C]NNC 112 as a marker for low DA tone as previously suggested by studies in patients with schizophrenia.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. De Keyser J, Ebinger G, Vauquelin G . Evidence for a widespread dopaminergic innervation of the human cerebral neocortex. Neurosci Lett 1989; 104: 281–285.

    Article  CAS  PubMed  Google Scholar 

  2. Hall H, Sedvall G, Magnusson O, Kopp J, Halldin C, Farde L . Distribution of D1- and D2-dopamine receptors, and dopamine and its metabolites in the human brain. Neuropsychopharmacology 1994; 11: 245–256.

    Article  CAS  PubMed  Google Scholar 

  3. Lidow MD, Goldman-Rakic PS, Rakic P, Gallagher DW . Autoradiographic comparison of D1-specific binding of [3H]SCH39166 and [3H]SCH23390 in the primate cerebral cortex. Brain Res 1990; 537: 349–354.

    Article  CAS  PubMed  Google Scholar 

  4. Dawson TM, McCabe RT, Stensaas SS, Wamsley JK . Autoradiographic evidence of [3H]SCH23390 binding sites in human prefrontal cortex (Brodmann's area 9). J Neurochem 1987; 49: 789–796.

    Article  CAS  PubMed  Google Scholar 

  5. Lawtho D, Hirsch JC, Crepel F . Dopamine modulation of synaptic transmission in rat prefrontal cortex: an in vitro electrophysiological study. Neurosci Res 1994; 21: 151–160.

    Article  CAS  Google Scholar 

  6. Seamans JK, Gorelova N, Durstewitz D, Yang CR . Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci 2001; 21: 3628–3638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yang CR, Seamans JK, Gorelova N . Developing a neuronal model for the pathophysiology of schizophrenia based on the nature of electrophysiological actions of dopamine in the prefrontal cortex. Neuropsychopharmacology 1999; 21: 161–194.

    Article  CAS  PubMed  Google Scholar 

  8. Yang CR, Seamans JK . Dopamine D1 receptor actions in layers V–VI rat prefrontal cortex neurons in vitro: modulation of dendritic–somatic signal integration. J Neurosci 1996; 16: 1922–1935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Guo N, Hwang DR, Lo ES, Huang YY, Laruelle M, Abi-Dargham A . Dopamine depletion and in vivo binding of PET D1 receptor radioligands: implications for imaging studies in schizophrenia. Neuropsychopharmacology 2003; 28: 1703–1711.

    Article  CAS  PubMed  Google Scholar 

  11. Jentsch JD, Taylor JR, Elsworth JD, Redmond Jr DE, Roth RH . Altered frontal cortical dopaminergic transmission in monkeys after subchronic phencyclidine exposure: involvement in frontostriatal cognitive deficits. Neuroscience 1999; 90: 823–832.

    Article  CAS  PubMed  Google Scholar 

  12. Tsukada H, Nishiyama S, Fukumoto D, Sato K, Kakiuchi T, Domino EF . Chronic NMDA antagonism impairs working memory, decreases extracellular dopamine, and increases D1 receptor binding in prefrontal cortex of conscious monkeys. Neuropsychopharmacology 2005; 30: 1861–1869.

    Article  CAS  PubMed  Google Scholar 

  13. Narendran R, Frankle WG, Keefe R, Gil R, Martinez D, Slifstein M et al. Altered prefrontal dopaminergic function in chronic recreational ketamine users. Am J Psychiatry 2005; 162: 2352–2359.

    Article  PubMed  Google Scholar 

  14. Sesack SR, Hawrylak VA, Matus C, Guido MA, Levey AI . 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lewis DA, Melchitzky DS, Sesack SR, Whitehead RE, Auh S, Sampson A . Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J Comp Neurol 2001; 432: 119–136.

    Article  CAS  PubMed  Google Scholar 

  16. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM . Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996; 6: 243–250.

    Article  CAS  PubMed  Google Scholar 

  17. Chen JS, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 2004; 75: 807–821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 2001; 98: 6917–6922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Goldberg TE, Egan MF, Gscheidle T, Coppola R, Weickert T, Kolachana BS et al. Executive subprocesses in working memory—relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Arch Gen Psychiatry 2003; 60: 889–896.

    Article  CAS  PubMed  Google Scholar 

  20. Gogos JA, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D et al. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci USA 1998; 95: 9991–9996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Halldin C, Foged C, Chou YH, Karlsson P, Swahn CG, Sandell J et al. Carbon-11-NNC 112: a radioligand for PET examination of striatal and neocortical D1-dopamine receptors. J Nucl Med 1998; 39: 2061–2068.

    CAS  PubMed  Google Scholar 

  22. Abi-Dargham A, Martinez D, Mawlawi O, Simpson N, Hwang DR, Slifstein M et al. Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: validation and reproducibility. J Cereb Blood Flow Metab 2000; 20: 225–243.

    Article  CAS  PubMed  Google Scholar 

  23. Woods RP, Mazziotta JC, Cherry SR . MRI–PET registration with automated algorithm. J Comput Assist Tomogr 1993; 17: 536–546.

    Article  CAS  PubMed  Google Scholar 

  24. Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR et al. Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D-2 receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 2001; 21: 1034–1057.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Innis RB, Cunningham VJ, Delforge J, Fujita M, Giedde A, Gunn RN et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007; 27: 1533–1539.

    Article  CAS  PubMed  Google Scholar 

  27. Hall H, Sedvall G, Magnusson O, Kopp J, Halldin C, Farde L . Distribution of D1- and D2-dopamine receptors, and dopamine and its metabolites in the human brain. Neuropsychopharmacology 1994; 11: 245–256.

    Article  CAS  PubMed  Google Scholar 

  28. Gogos JA, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D et al. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci USA 1998; 95: 9991–9996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ . Catechol-O-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci 2004; 24: 5331–5335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Blasi G, Mattay VS, Bertolino A, Elvevag B, Callicott JH, Das S et al. Effect of catechol-O-methyltransferase val158met genotype on attentional control. J Neurosci 2005; 25: 5038–5045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bertolino A, Caforio G, Blasi G, Rampino A, Sinibaldi L, Douzgou S et al. COMT Val158Met polymorphism predicts negative symptoms response to treatment with olanzapine in schizophrenia. Biol Psychiatry 2007; 61: 13S.

    Article  Google Scholar 

  32. Drabant EM, Hariri AR, Meyer-Lindenberg A, Munoz KE, Mattay VS, Kolachana BS et al. Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation. Arch Gen Psychiatry 2006; 63: 1396–1406.

    Article  CAS  PubMed  Google Scholar 

  33. Matsumoto M, Weickert CS, Akil M, Lipska BK, Hyde TM, Herman MM et al. Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience 2003; 116: 127–137.

    Article  CAS  PubMed  Google Scholar 

  34. Masuda M, Tsunoda M, Imai K . High-performance liquid chromatography-fluorescent assay of catechol-O-methyltransferase activity in rat brain. Anal Bioanal Chem 2003; 376: 1069–1073.

    Article  CAS  PubMed  Google Scholar 

  35. Slifstein M, Kegeles LS, Gonzales R, Frankle WG, Xu XY, Laruelle M et al. [C-11] NNC 112 selectivity for dopamine D-1 and serotonin 5-HT2A receptors: a PET study in healthy human subjects. J Cereb Blood Flow Metab 2007; 27: 1733–1741.

    Article  CAS  PubMed  Google Scholar 

  36. Li T, Sham PC, Vallada H, Xie T, Tang X, Murray RM et al. Preferential transmission of the high activity allele of COMT in schizophrenia. Psychiatr Genet 1996; 6: 131–133.

    Article  CAS  PubMed  Google Scholar 

  37. Herken H, Erdal ME . Catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association between symptomatology and prognosis. Psychiatr Genet 2001; 11: 105–109.

    Article  CAS  PubMed  Google Scholar 

  38. Ohmori O, Shinkai T, Kojima H, Terao T, Suzuki T, Mita T et al. Association study of a functional catechol-O-methyltransferase gene polymorphism in Japanese schizophrenics. Neurosci Lett 1998; 243: 109–112.

    Article  CAS  PubMed  Google Scholar 

  39. Daniels JK, Williams NM, Williams J, Jones LA, Cardno AG, Murphy KC et al. No evidence for allelic association between schizophrenia and a polymorphism determining high or low catechol O-methyltransferase activity. Am J Psychiatry 1996; 153: 268–270.

    Article  CAS  PubMed  Google Scholar 

  40. de Chaldee M, Corbex M, Campion D, Jay M, Samolyk D, Petit M et al. No evidence for linkage between COMT and schizophrenia in a French population. Psychiatry Res 2001; 102: 87–90.

    Article  CAS  PubMed  Google Scholar 

  41. Wei J, Hemmings GP . Lack of evidence for association between the COMT locus and schizophrenia. Psychiatr Genet 1999; 9: 183–186.

    Article  CAS  PubMed  Google Scholar 

  42. Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY et al. Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol Psychiatry 2005; 57: 139–144.

    Article  CAS  PubMed  Google Scholar 

  43. Meyer-Lindenberg A, Nichols T, Callicott JH, Ding J, Kolachana B, Buckholtz J et al. Impact of complex genetic variation in COMT on human brain function. Mol Psychiatry 2006; 11: 867–877.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the excellent technical support provided by Elizabeth Hackett in PET acquisition, John Castrillon in radioligand preparation, Jennifer Bae in plasma metabolite analysis and Erica Scher in data analysis.

Author information

Authors and Affiliations

  1. Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    M Slifstein, P Tabares, M Duvall, W Gordon Frankle, M Laruelle & A Abi-Dargham

  2. Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, USA

    B Kolachana & D R Weinberger

  3. Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    E H Simpson

  4. Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA

    B Cheng

  5. Molecular Imaging, Glaxo-SmithKline, London, UK

    M Laruelle

  6. Department of Radiology, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    A Abi-Dargham

Authors
  1. M Slifstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B Kolachana
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E H Simpson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Tabares
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Duvall
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W Gordon Frankle
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D R Weinberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Laruelle
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A Abi-Dargham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Slifstein.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Slifstein, M., Kolachana, B., Simpson, E. et al. COMT genotype predicts cortical-limbic D1 receptor availability measured with [11C]NNC112 and PET. Mol Psychiatry 13, 821–827 (2008). https://doi.org/10.1038/mp.2008.19

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2008.19

Keywords

This article is cited by

Search

Advanced search

Quick links