Skip to main content
SpringerLink
Log in

Cortical NMDA Receptor Expression in Human Chronic Alcoholism: Influence of the TaqIA Allele of ANKK1

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Real-time RT-PCR normalized to GAPDH was used to assay N-methyl-d-aspartate (NMDA) receptor NR1, NR2A and NR2B subunit mRNA in human autopsy cortex tissue from chronic alcoholics with and without comorbid cirrhosis of the liver and matched controls. Subunit expression was influenced by the subject’s genotype. The TaqIA polymorphism selectively modulated NMDA receptor mean transcript expression in cirrhotic-alcoholic superior frontal cortex, in diametrically opposite ways in male and female subjects. Genetic make-up may differentially influence vulnerability to brain damage by altering the excitation: inhibition balance, particularly in alcoholics with comorbid cirrhosis of the liver. The TaqIA polymorphism occurs within the poorly characterised ankyrin-repeat containing kinase 1 (ANKK1) gene. Using PCR, ANKK1 mRNA transcript was detected in inferior temporal, occipital, superior frontal and primary motor cortex of control human brain. ANKK1 expression may mediate the influence of the TaqIA polymorphism on phenotype.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kril JJ, Harper CG (1989) Neuronal counts from four cortical regions of alcoholic brains. Acta Neuropathol 79:200–204. doi:10.1007/BF00294379

    Article  PubMed  CAS  Google Scholar 

  2. Dodd PR (2002) Excited to death: different ways to lose your neurones. Biogerontology 3:51–56. doi:10.1023/A:1015255312948

    Article  PubMed  CAS  Google Scholar 

  3. Johnston GAR, Curtis DR, De Groat WC et al (1968) Central actions of ibotenic acid and muscimol. Biochem Pharmacol 17:2488–2489. doi:10.1016/0006-2952(68)90141-X

    Article  PubMed  CAS  Google Scholar 

  4. Johnston GAR (1971) Muscimol and the uptake of γ-aminobutyric acid by rat brain slices. Psychopharmacology (Berl) 22:230–233. doi:10.1007/BF00401785

    Article  CAS  Google Scholar 

  5. Balcar VJ, Johnston GAR (1973) High affinity uptake of transmitters: studies on the uptake of l-aspartate, GABA, l-glutamate and glycine in cat spinal cord. J Neurochem 20:529–539. doi:10.1111/j.1471-4159.1973.tb12152.x

    Article  PubMed  CAS  Google Scholar 

  6. Krogsgaard-Larsen P, Johnston GAR (1978) Structure-activity studies on the inhibition of GABA binding to rat brain membranes by muscimol and related compounds. J Neurochem 30:1377–1382. doi:10.1111/j.1471-4159.1978.tb10469.x

    Article  PubMed  CAS  Google Scholar 

  7. Andrews PR, Johnston GAR (1979) GABA agonists and antagonists. Biochem Pharmacol 28:2697–2702. doi:10.1016/0006-2952(79)90549-5

    Article  PubMed  CAS  Google Scholar 

  8. Johnston GAR (1994) GABA receptors: as complex as ABC? Clin Exp Pharmacol Physiol 21:521–526. doi:10.1111/j.1440-1681.1994.tb02550.x

    Article  PubMed  CAS  Google Scholar 

  9. Mitrovic AD, Johnston GAR (1994) Regional differences in the inhibition of L-glutamate and l-aspartate sodium-dependent high affinity uptake systems in rat CNS synaptosomes by l-trans-pyrrolidine-2, 4-dicarboxylate, threo-3-hydroxy-d-aspartate and d-aspartate. Neurochem Int 24:583–588. doi:10.1016/0197-0186(94)90011-6

    Article  PubMed  CAS  Google Scholar 

  10. Johnston GAR (2002) Medicinal chemistry and molecular pharmacology of GABAC receptors. Curr Top Med Chem 2:903–913. doi:10.2174/1568026023393453

    Article  PubMed  CAS  Google Scholar 

  11. Ridge JP, Dodd PR (2008) Glutamate and ethanol: the role of ionotropic NMDA glutamate receptors in alcoholism. In: Paley BF, Warfield TE (eds) Amino acid receptor research. Nova Science Publishers, New York, pp 367–377

    Google Scholar 

  12. Ridge JP, Ho AM-C, Innes DJ et al (2008) The expression of NMDA receptor subunit mRNA in human chronic alcoholics. Ann N Y Acad Sci 1139:10–19

    Article  PubMed  CAS  Google Scholar 

  13. Pierce RC, Kumaresan V (2006) The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev 30:215–238. doi:10.1016/j.neubiorev.2005.04.016

    Article  PubMed  CAS  Google Scholar 

  14. Blum K, Noble EP, Sheridan PJ et al (1993) Genetic predisposition in alcoholism: association of the D2 dopamine receptor TaqI B1 RFLP with severe alcoholics. Alcohol 10:59–67. doi:10.1016/0741-8329(93)90054-R

    Article  PubMed  CAS  Google Scholar 

  15. Noble EP, Syndulko K, Fitch RJ et al (1994) D2 dopamine receptor TaqI A alleles in medically ill alcoholic and nonalcoholic patients. Alcohol Alcohol 29:729–744

    PubMed  CAS  Google Scholar 

  16. Ishiguro H, Arinami T, Saito T et al (1998) Association study between the –141C Ins/Del and TaqI A polymorphisms of the dopamine D2 receptor gene and alcoholism. Alcohol Clin Exp Res 22:845–848

    PubMed  CAS  Google Scholar 

  17. Lu RB, Lee JF, Ko HC et al (2001) Dopamine D2 receptor gene (DRD2) is associated with alcoholism with conduct disorder. Alcohol Clin Exp Res 25:177–184. doi:10.1111/j.1530-0277.2001.tb02196.x

    Article  PubMed  CAS  Google Scholar 

  18. Madrid GA, MacMurray J, Lee JW et al (2001) Stress as a mediating factor in the association between the DRD2 TaqI polymorphism and alcoholism. Alcohol 23:117–122. doi:10.1016/S0741-8329(00)00138-5

    Article  PubMed  CAS  Google Scholar 

  19. Young RM, Lawford BR, Noble EP et al (2002) Harmful drinking in military veterans with post-traumatic stress disorder: association with the D2 dopamine receptor A1 allele. Alcohol Alcohol 37:451–456. doi:10.1093/alcalc/37.5.451

    PubMed  CAS  Google Scholar 

  20. Hallikainen T, Hietala J, Kauhanen J et al (2003) Ethanol consumption and DRD2 gene TaqI a polymorphism among socially drinking males. Am J Med Genet A 119A:152–155. doi:10.1002/ajmg.a.20139

    Article  PubMed  Google Scholar 

  21. Berggren U, Fahlke C, Aronsson E et al (2006) The taqI DRD2 A1 allele is associated with alcohol-dependence although its effect size is small. Alcohol Alcohol 41:479–485. doi:10.1093/alcalc/agl043

    PubMed  CAS  Google Scholar 

  22. Dick DM, Wang JC, Plunkett J et al (2007) Family-based association analyses of alcohol dependence phenotypes across DRD2 and neighboring gene ANKK1. Alcohol Clin Exp Res 31:1645–1653. doi:10.1111/j.1530-0277.2007.00470.x

    Article  PubMed  CAS  Google Scholar 

  23. Ponce G, Hoenicka J, Jimenez-Arriero MA et al (2008) DRD2 and ANKK1 genotype in alcohol-dependent patients with psychopathic traits: association and interaction study. Br J Psychiatry 193:121–125. doi:10.1192/bjp.bp.107.041582

    Article  PubMed  CAS  Google Scholar 

  24. Gelernter J, O’Malley S, Risch N et al (1991) No association between an allele at the D2 dopamine receptor gene (DRD2) and alcoholism. JAMA 266:1801–1807. doi:10.1001/jama.266.13.1801

    Article  PubMed  CAS  Google Scholar 

  25. Chen CH, Chien SH, Hwu HG (1996) Lack of association between TaqI A1 allele of dopamine D2 receptor gene and alcohol-use disorders in atayal natives of Taiwan. Am J Med Genet C Sem Med Genet 67C:488–490

    Article  Google Scholar 

  26. Matsushita S, Muramatsu T, Murayama M et al (2001) Alcoholism, ALDH2*2 allele and the A1 allele of the dopamine D2 receptor gene: an association study. Psychiatry Res 104:19–26. doi:10.1016/S0165-1781(01)00290-6

    Article  PubMed  CAS  Google Scholar 

  27. Shaikh KJ, Naveen D, Sherrin T et al (2001) Polymorphisms at the DRD2 locus in early onset alcohol dependence in the Indian population. Addict Biol 6:331–335. doi:10.1080/13556210020077055

    Article  PubMed  Google Scholar 

  28. Yang BZ, Kranzler HR, Zhao H et al (2007) Association of haplotypic variants in DRD2, ANKK1, TTC12 and NCAM1 to alcohol dependence in independent case control and family samples. Hum Mol Genet 16:2844–2853. doi:10.1093/hmg/ddm240

    Article  PubMed  CAS  Google Scholar 

  29. Noble EP (2003) D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. Am J Med Genet B Neuropsychiatr Genet 116B:103–125. doi:10.1002/ajmg.b.10005

    Article  PubMed  Google Scholar 

  30. Young RM, Lawford BR, Nutting A et al (2004) Advances in molecular genetics and the prevention and treatment of substance misuse: implications of association studies of the A1 allele of the D2 dopamine receptor gene. Addict Behav 29:1275–1294. doi:10.1016/j.addbeh.2004.06.012

    Article  PubMed  Google Scholar 

  31. Munafò MR, Matheson IJ, Flint J (2007) Association of the DRD2 gene Taq1A polymorphism and alcoholism: a meta-analysis of case-control studies and evidence of publication bias. Mol Psychiatry 12:454–461

    PubMed  Google Scholar 

  32. Neville MJ, Johnstone EC, Walton RT (2004) Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat 23:540–545. doi:10.1002/humu.20039

    Article  PubMed  CAS  Google Scholar 

  33. Fossella J, Green AE, Fan J (2006) Evaluation of a structural polymorphism in the ankyrin repeat and kinase domain containing 1 (ANKK1) gene and the activation of executive attention networks. Cogn Affect Behav Neurosci 6:71–78. doi:10.3758/CABN.6.1.71

    Article  PubMed  Google Scholar 

  34. Dodd PR, Hardy JA, Baig EB et al (1986) Optimization of freezing, storage, and thawing conditions for the preparation of metabolically active synaptosomes from frozen rat and human brain. Neurochem Pathol 4:177–198. doi:10.1007/BF02834357

    Article  PubMed  CAS  Google Scholar 

  35. Grandy DK, Zhang Y, Civelli O (1993) PCR detection of the TaqA RFLP at the DRD2 locus. Hum Mol Genet Genet 2:2197. doi:10.1093/hmg/2.12.2197-a

    Article  Google Scholar 

  36. Castiglione CM, Deinard AS, Speed WC et al (1995) Evolution of haplotypes at the DRD2 locus. Am J Hum Genet 57:1445–1456

    PubMed  CAS  Google Scholar 

  37. Pohjalainen T, Rinne JO, Nagren K et al (1998) The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry 3:256–260. doi:10.1038/sj.mp.4000350

    Article  PubMed  CAS  Google Scholar 

  38. Laine TP, Ahonen A, Rasanen P et al (2001) The A1 allele of the D2 dopamine receptor gene is associated with high dopamine transporter density in detoxified alcoholics. Alcohol Alcohol 36:262–265. doi:10.1093/alcalc/36.3.262

    PubMed  CAS  Google Scholar 

  39. Limosin F, Gorwood P, Loze JY et al (2002) Male limited association of the dopamine receptor D2 gene TaqIA polymorphism and alcohol dependence. Am J Med Genet 112:343–346. doi:10.1002/ajmg.10712

    Article  PubMed  Google Scholar 

  40. Munafò MR, Johnstone EC, Welsh KI et al (2005) Association between the DRD2 gene TaqIA (C32806T) polymorphism and alcohol consumption in social drinkers. Pharmacogenomics J 5:96–101. doi:10.1038/sj.tpj.6500294

    Article  PubMed  CAS  Google Scholar 

  41. Reuter M, Schmitz A, Corr P et al (2006) Molecular genetics support Gray’s personality theory: the interaction of COMT and DRD2 polymorphisms predicts the behavioural approach system. Int J Neuropsychopharmacol 9:155–166. doi:10.1017/S1461145705005419

    Article  PubMed  CAS  Google Scholar 

  42. Blum K, Sheridan PJ, Wood RC et al (1995) Dopamine D2 receptor gene variants: association and linkage studies in impulsive-addictive-compulsive behavior. Pharmacogenetics 5:121–141. doi:10.1097/00008571-199506000-00001

    Article  PubMed  CAS  Google Scholar 

  43. Comings DE (1996) Genetic factors in drug abuse and dependence. NIDA Monogr 159:16–38

    CAS  Google Scholar 

  44. Comings DE, Gade R, Wu S et al (1997) Studies of the potential role of the dopamine D1 receptor gene in addictive behaviors. Mol Psychiatry 2:44–56. doi:10.1038/sj.mp.4000207

    Article  PubMed  CAS  Google Scholar 

  45. Comings DE, Blum K (2000) Reward deficiency syndrome: genetic aspects of behavioral disorders. Prog Brain Res 126:325–341. doi:10.1016/S0079-6123(00)26022-6

    Article  PubMed  CAS  Google Scholar 

  46. Pritchard C, Cox M (2007) Comparison of problematic behaviours of 10th, 11th year Southern English adolescents in 1985 and 2005. Part 1: trends in gender behaviour. Int J Adolesc Med Health 19:127–140

    PubMed  Google Scholar 

  47. Barrick D, Ferreiro DU, Komives EA (2008) Folding landscapes of ankyrin repeat proteins: experiments meet theory. Curr Opin Struct Biol 18:27–34. doi:10.1016/j.sbi.2007.12.004

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Neuropathologists from the Queensland Brain Bank and the NSW Tissue Resource Centre for the tissue samples, and the next of kin for informed written consent. The tissue banks are part of Australian Brain Bank Network supported by the National Health and Medical Research Council (NHMRC). The NSW Centre and the Australian Brain Donor Programme are supported by The University of Sydney, NHMRC, Schizophrenia Research Institute, National Institutes of Alcoholism and Alcohol Abuse USA (NIAAA), and NSW Department of Health. Financial support for this study was provided by the NIAAA under grant NIH AA12404 and the NHMRC under grant #401551.

Author information

Authors and Affiliations

  1. School of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, Building #76, Brisbane, QLD, 4072, Australia

    Justin P. Ridge & Peter R. Dodd

Authors
  1. Justin P. Ridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter R. Dodd
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter R. Dodd.

Additional information

Special issue article in honor of Dr. Graham Johnston.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ridge, J.P., Dodd, P.R. Cortical NMDA Receptor Expression in Human Chronic Alcoholism: Influence of the TaqIA Allele of ANKK1 . Neurochem Res 34, 1775–1782 (2009). https://doi.org/10.1007/s11064-009-9941-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-009-9941-8

Keywords

Search

Navigation