NeuroMolecular Medicine

, Volume 2, Issue 3, pp 281–287 | Cite as

A drosophila model for attention deficit hyperactivity disorder (ADHD)

No evidence of association with PRKG1 gene
  • Vincenzo De Luca
  • Pierandrea Muglia
  • Umesh Jain
  • Vincenzo S. Basile
  • Marla B. Sokolowski
  • James L. Kennedy
Original Research

Abstract

Attention deficit hyperactivity disorder (ADHD) is a prevalent psychiatric condition in children and follow up studies have indicated that 22–33% of patients continue to suffer from ADHD during late adolescence and adulthood. The action of psychostimulant drugs may be determined by additional mechanisms beyond the dopamine transporter and receptors. We are exploring new methodology for discovering these mechanisms. For example, in Drosophila, such an additional determinant of psychostimulant action could be protein kinase G (PKG) that affects food-search behavior. Here we initiated studies with the human homologue of PKG, the PRKG1 gene. The aim of this study was to investigate for the presence of linkage disequilibrium between the protein kinase G gene (PRKG1) and adult ADHD in a sample of nuclear families. Genotyping data for the C2276T polymorphism were analyzed using the Transmission Disequilibrium Test (TDT). Sixty three nuclear families were informative for the TDT on C2276T polymorphism, which showed no preferential transmission of either allele (chi-square=0.778, df=1, p=0.316). These findings exclude a direct involvement of this genetic marker of the Protein kinase G gene in the pathogenesis of ADHD.

Index Entries

Adult ADHD PRKG1 (protein kinase G gene) PKG (CGMP-dependent protein kinase) polymorphism linkage disequilibrium TDT (transmission/disequilibrium test) genetics 

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References

  1. 1.
    American Psychiatric Association. (1994) Diagnostic and Statistical Manual of Mental Disorder, 4th ed. (DSM-IV). Washington, American Psychiatric Association.Google Scholar
  2. 2.
    Hill, J. C. and Schoener, E. P. (1996) Age-dependent decline of attention deficit hyperactivity disorder Am. J. Psychiatry 153, 1143–1146.PubMedGoogle Scholar
  3. 3.
    Barr C. L., Swanson J., and Kennedy J. L. (2001) Molecular genetics of ADHD. In: Attention, Genes and ADHD. Levy F. and Hay D. (Eds). Taylor & Francis, Inc. 173–195.Google Scholar
  4. 4.
    Faraone S. V., Biederman J., and Monuteaux M. C. (2000) Toward guidelines for pedigree selection in genetic studies of attention deficit hyperactivity disorder. Genet. Epidemiol. 18, 1–16.PubMedCrossRefGoogle Scholar
  5. 5.
    Weiss G., Hechtman L., Milroy T., et al. (1985) Psychiatric status of hyperactives as adults: a controlled prospective 15-year follow-up of 63 hyperactive children. J. Am. Acad. Child. Adolesc. Psychiatry 24, 211–220.CrossRefGoogle Scholar
  6. 6.
    Biederman J., Mick E., and Faraone S. V. (2000) Age-dependent decline of symptoms of attention defict hyperactivity disorder: impact of remission definition and symptom type. Am. J. Psychiatry 157, 816–818.PubMedCrossRefGoogle Scholar
  7. 7.
    Brown T. E. (1996) The Brown Deficit Disorder Scale. San Antonio, The Psychological Corporation.Google Scholar
  8. 8.
    Ward M. F., Wender P. H., and Reimherr F. W. (1993) The Wender Utah Rating Scale: an aid in the retrospective diagnosis of childhood attention deficit hyperactivity disorder. Am. J. Psychiatry 150, 885–890.PubMedGoogle Scholar
  9. 9.
    Wilens T., Spencer T. J., and Biederman J. (1998) Pharmacotherapy of ADHD in adults. CNS Drugs 9, 347–356.CrossRefGoogle Scholar
  10. 10.
    Faraone S. V., Doyle A. E., Mick E., et al. (2001) Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder. Am. J. Psychiatry 158, 1052–1057.PubMedCrossRefGoogle Scholar
  11. 11.
    Cook E. H. Jr., Stein M. A., Krasowski M. D., et al. (1995) Association of attention-deficit disorder and the dopamine transporter gene. Am. J. Hum. Genet. 56, 993–998.PubMedGoogle Scholar
  12. 12.
    Muglia P., Jain U., Macciardi F., et al. (2000) Adult Attention Deficit Hyperactivity Disorder and the Dopamine D4 Receptor Gene. Am. J. Med. Genet. 96, 273–277.PubMedCrossRefGoogle Scholar
  13. 13.
    Muglia P., Jain U., and Kennedy J. L. (2002) A transmission disequilibrium test of the Ser9/Gly dopamine D3 receptor gene polymorphism in adult attention-deficit hyperactivity disorder. Behav. Brain Res. 130, 91–95.PubMedCrossRefGoogle Scholar
  14. 14.
    Faraone S. V., Biederman J., Weiffenbach B., et al. (1999) Dopamine D4 gene 7-repeat allele and attention deficit hyperactivity disorder. Am. J. Psychiatry 1156, 768–770.Google Scholar
  15. 15.
    Wilson M. C. (2000) Coloboma mouse mutant as an animal model of hyperkinesis and attention deficit hyperactivity disorder. Neurosci. Biobehav. Rev. 24, 51–57.PubMedCrossRefGoogle Scholar
  16. 16.
    Barr C. L., Feng Y., Wigg K., et al. (2000) Identification of DNA variants in the SNAP-25 gene and linkage study of these polymorphisms and attention-deficit hyperactivity disorder. Mol. Psychiatry 5, 405–409.PubMedCrossRefGoogle Scholar
  17. 17.
    Mill J., Curran S., Kent L., et al. (2002) Association study of a SNP-25 microsatellite and attention deficit hyperactivity disorder. Am. J. Med. Genet. 114, 269–271.PubMedCrossRefGoogle Scholar
  18. 18.
    Yoshihara M., Ensminger A. W., and Littleton J. T., et al. (2001) Neurobiology and the Drosophila genome. Funct. Intrgr. Genomics. 1, 235–240.CrossRefGoogle Scholar
  19. 19.
    Osborne K. A., Robichon A., Burgess E., et al. (1997) Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila. Science 277, 834–836.PubMedCrossRefGoogle Scholar
  20. 20.
    Sokolowsky M. B. and Riedl C. (1999) Behavior—genetic and molecular analysis of naturally occurring variation in Drosophila larval foraging behavior. In: Molecular-Genetic for Brain and Behaviour. Gerlai R. and Crusio W. (Eds.) Elsevier Scientific, 517–532.Google Scholar
  21. 21.
    Engel J. E., Xie X. J., Sokolowski M. B., et al. (2000) A cGMP dependent protein kinase gene, foraging, modifies habituation of the giant fiber escape response in Drosophila. Learning and Memory 7, 341–352.PubMedCrossRefGoogle Scholar
  22. 22.
    Butt E., Geiger J., Jarchau T., et al. (1993) The cGMP-dependent protein kinase—gene, protein, and function. Neurochem. Res. 18, 27–42.PubMedCrossRefGoogle Scholar
  23. 23.
    Hall J. C. (1994) Pleiotropy of behavioral genes. In: Flexibility and Constraint in Behavioral Systems. Greenspan R. J. and Kyriacou C. P. (Eds.) Wiley: 15–28.Google Scholar
  24. 24.
    Paupardin-Tritsch D., Hammond C., Gerschenfeld H. M., et al. (1986) cGMP-dependent protein kinase enhances Ca2+ current and potentiates the serotonin-induced Ca2+ current increase in snail neurons. Nature 323, 812–814.PubMedCrossRefGoogle Scholar
  25. 25.
    Woody C. D., Bartfai T., Gruen E., et al. (1986) Intracellular injection of cGMP-dependent protein kinase results in increased input resistance in neurons of the mammalian motor cortex. Brain Res. 386, 379–385.PubMedCrossRefGoogle Scholar
  26. 26.
    Zhuo M., Hu Y., Schultz C., et al. (1994) Role of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation. Nature 368, 635–639.PubMedCrossRefGoogle Scholar
  27. 27.
    Arancio O., Kandel E. R., Hawkins R. D., et al. (1995) Activity-dependent long-term enhancement of transmitter release by presynaptic 3′,5′-cyclic GMP in cultured hippocampal neurons. Nature 376, 74–80.PubMedCrossRefGoogle Scholar
  28. 28.
    Orstavik S., Natarajan V., Tasken K., et al. (1997) Characterization of the human gene encoding the type I alpha and type I beta cGMP-dependent protein kinase (PRKG1). Genomics 42, 311–318.PubMedCrossRefGoogle Scholar
  29. 28a.
    Orstavik S., Sandberg M., Berube D., et al. (1992) Localization of the human gene for the type I cyclic GMP-dependent protein kinase to chromosome 10. Cytogenet. Cell Genet 59, 270–273.PubMedCrossRefGoogle Scholar
  30. 29.
    Cornwell T. L., Arnold E., Boerth N. J., et al. (1994) Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP-dependent protein kinase by cGMP. Am. J. Physiol. 267, C1405–1413.PubMedGoogle Scholar
  31. 30.
    Wyatt T. A., Lincoln T. M., Pryzwansky K. B., et al. (1993) Regulation of human neutrophil degranulation by LY-83583 and L-arginine: role of cGMP-dependent protein kinase. Am. J. Physiol. 265, C201–211.PubMedGoogle Scholar
  32. 31.
    Risch N. and Merikangas K. (1996). The future of genetics studies on complex human diseases. Science 273, 1516–1517.PubMedCrossRefGoogle Scholar
  33. 32.
    Spielman R. S., McGinnis R. E., and Ewens W. J. (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52, 506–516.PubMedGoogle Scholar
  34. 33.
    Conners C. K., Erhardt D., and Sparrow E. (1997) CAARS. North Tonawanda, Multi-Health Systems, Inc.Google Scholar
  35. 34.
    Conners C. K. (1993) The Conners Continuous Performance Test. North Tonawanda, Multi-Health System, Inc.Google Scholar
  36. 34a.
    Weschler D. I. (1997) Weschler Adult Intelligence Scale 3rd Edition. New York, Psychological Corporation.Google Scholar
  37. 35.
    Lahiri D. K. and Nurnberger J. I., Jr. (1991) A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res. 19, 5444.PubMedCrossRefGoogle Scholar
  38. 36.
    Ebstein R. P., Novick O., Umansky R., et al. (1996) Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. Nat. Genet. 12, 78–80.PubMedCrossRefGoogle Scholar
  39. 37.
    Leckman J. F., Zhang L., Alsobrook J. P., et al. (2001) Symptom dimensions in obsessive-compulsive disorder: toward quantitative phenotypes. Am. J. Med. Genet. 105, 28–30.PubMedCrossRefGoogle Scholar
  40. 38.
    Rowe D. C., Stever C., Chase D., et al. (2001) Two dopamine genes related to reports of childhood retrospective inattention and conduct disorder symptoms. Mol. Psychiatry 6, 429–433.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2002

Authors and Affiliations

  • Vincenzo De Luca
    • 1
    • 3
  • Pierandrea Muglia
    • 1
    • 2
  • Umesh Jain
    • 2
  • Vincenzo S. Basile
    • 1
  • Marla B. Sokolowski
    • 4
  • James L. Kennedy
    • 1
  1. 1.Neurogenetics SectionUniversity of TorontoTorontoCanada
  2. 2.Adult ADHD Clinic, Clarke Site, Centre for Addiction and Mental Health, Department of PsychiatryUniversity of TorontoTorontoCanada
  3. 3.Department of PsychiatrySecond University of NaplesNaplesItaly
  4. 4.Department of ZoologyUniversity of Toronto at MississaugaMississauga

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