Skip to main content

Advertisement

SpringerLink
Log in

Implication of Genes for the N-Methyl-d-Aspartate (NMDA) Receptor in Substance Addictions

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Drug dependence is a chronic brain disease with harmful consequences for both individual users and society. Glutamate is a primary excitatory neurotransmitter in the brain, and both in vivo and in vitro experiments have implicated N-methyl-d-aspartate (NMDA) receptor, a glutamate receptor, as an element in various types of addiction. Recent findings from genetics-based approaches such as genome-wide linkage, candidate gene association, genome-wide association (GWA), and next-generation sequencing have demonstrated the significant association of NMDA receptor subunit genes such as GluN3A, GluN2B, and GluN2A with various addiction-related phenotypes. Of these genes, GluN3A has been the most studied, and it has been revealed to play crucial roles in the etiology of addictions. In this communication, we provide an updated view of the genetic effects of NMDA receptor subunit genes and their functions in the etiology of addictions based on the findings from investigation of both common and rare variants as well as SNP–SNP interactions. To better understand the molecular mechanisms underlying addiction-related behaviors and to promote the development of specific medicines for the prevention and treatment of addictions, current efforts aim not only to identify more causal variants in NMDA receptor subunits by using large independent samples but also to reveal the molecular functions of these variants in addictions.

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. WHO (2008) Report on the global tobacco epidemic, 2008: the MPOWER package. World Health Organization, Geneva

    Google Scholar 

  2. Ho MK, Goldman D, Heinz A, Kaprio J, Kreek MJ, Li MD, Munafo MR, Tyndale RF (2010) Breaking barriers in the genomics and pharmacogenetics of drug addiction. Clin Pharmacol Ther 88(6):779–791. https://doi.org/10.1038/clpt.2010.175

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Li MD, Burmeister M (2009) New insights into the genetics of addiction. Nat Rev Genet 10(4):225–231. https://doi.org/10.1038/nrg2536

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Goldman D, Oroszi G, Ducci F (2005) The genetics of addictions: uncovering the genes. Nat Rev Genet 6(7):521–532. https://doi.org/10.1038/nrg1635

    Article  PubMed  CAS  Google Scholar 

  5. Wang JC, Kapoor M, Goate AM (2012) The genetics of substance dependence. Annu Rev Genomics Hum Genet 13(1):241–261. https://doi.org/10.1146/annurev-genom-090711-163844

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Yu C, McClellan J (2016) Genetics of substance use disorders. Child Adolesc Psychiatr Clin N Am 25(3):377–385. https://doi.org/10.1016/j.chc.2016.02.002

    Article  PubMed  Google Scholar 

  7. Li MD, Cheng R, Ma JZ, Swan GE (2003) A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction 98(1):23–31. https://doi.org/10.1046/j.1360-0443.2003.00295.x

    Article  PubMed  Google Scholar 

  8. Gelernter J, Kranzler HR (2009) Genetics of alcohol dependence. Hum Genet 126(1):91–99. https://doi.org/10.1007/s00439-009-0701-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Kauer JA, Malenka RC (2007) Synaptic plasticity and addiction. Nat Rev Neurosci 8(11):844–858. https://doi.org/10.1038/nrn2234

    Article  PubMed  CAS  Google Scholar 

  10. Luscher C, Malenka RC (2011) Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69(4):650–663. https://doi.org/10.1016/j.neuron.2011.01.017

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Chandrasekar R (2013) Alcohol and NMDA receptor: current research and future direction. Front Mol Neurosci 6:14. https://doi.org/10.3389/fnmol.2013.00014

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Follesa P, Ticku MK (1995) Chronic ethanol treatment differentially regulates NMDA receptor subunit mRNA expression in rat brain. Brain Res Mol Brain Res 29(1):99–106. https://doi.org/10.1016/0169-328X(94)00235-7

    Article  PubMed  CAS  Google Scholar 

  13. Follesa P, Ticku MK (1996) Chronic ethanol-mediated up-regulation of the N-methyl-D-aspartate receptor polypeptide subunits in mouse cortical neurons in culture. J Biol Chem 271(23):13297–13299. https://doi.org/10.1074/jbc.271.23.13297

    Article  PubMed  CAS  Google Scholar 

  14. Follesa P, Ticku MK (1996) NMDA receptor upregulation: molecular studies in cultured mouse cortical neurons after chronic antagonist exposure. J Neurosci : Off J Soc Neurosci 16(7):2172–2178

    Article  CAS  Google Scholar 

  15. Saal D, Dong Y, Bonci A, Malenka RC (2003) Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37(4):577–582. https://doi.org/10.1016/S0896-6273(03)00021-7

    Article  PubMed  CAS  Google Scholar 

  16. Gipson CD, Reissner KJ, Kupchik YM, Smith AC, Stankeviciute N, Hensley-Simon ME, Kalivas PW (2013) Reinstatement of nicotine seeking is mediated by glutamatergic plasticity. Proc Natl Acad Sci U S A 110(22):9124–9129. https://doi.org/10.1073/pnas.1220591110

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ungless MA, Whistler JL, Malenka RC, Bonci A (2001) Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411(6837):583–587. https://doi.org/10.1038/35079077

    Article  PubMed  CAS  Google Scholar 

  18. Mameli M, Bellone C, Brown MT, Luscher C (2011) Cocaine inverts rules for synaptic plasticity of glutamate transmission in the ventral tegmental area. Nat Neurosci 14(4):414–416. https://doi.org/10.1038/nn.2763

    Article  PubMed  CAS  Google Scholar 

  19. Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14(6):383–400. https://doi.org/10.1038/nrn3504

    Article  PubMed  CAS  Google Scholar 

  20. Kaniakova M, Krausova B, Vyklicky V, Korinek M, Lichnerova K, Vyklicky L, Horak M (2012) Key amino acid residues within the third membrane domains of NR1 and NR2 subunits contribute to the regulation of the surface delivery of N-methyl-D-aspartate receptors. J Biol Chem 287(31):26423–26434. https://doi.org/10.1074/jbc.M112.339085

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Hu XJ, Follesa P, Ticku MK (1996) Chronic ethanol treatment produces a selective upregulation of the NMDA receptor subunit gene expression in mammalian cultured cortical neurons. Brain Res Mol Brain Res 36(2):211–218

    Article  PubMed  CAS  Google Scholar 

  22. Kalluri HS, Mehta AK, Ticku MK (1998) Up-regulation of NMDA receptor subunits in rat brain following chronic ethanol treatment. Brain Res Mol Brain Res 58(1–2):221–224. https://doi.org/10.1016/S0169-328X(98)00112-0

    Article  PubMed  CAS  Google Scholar 

  23. Hardy PA, Chen W, Wilce PA (1999) Chronic ethanol exposure and withdrawal influence NMDA receptor subunit and splice variant mRNA expression in the rat cerebral cortex. Brain Res 819(1–2):33–39. https://doi.org/10.1016/S0006-8993(98)01340-7

    Article  PubMed  CAS  Google Scholar 

  24. Narita M, Soma M, Mizoguchi H, Tseng LF, Suzuki T (2000) Implications of the NR2B subunit-containing NMDA receptor localized in mouse limbic forebrain in ethanol dependence. Eur J Pharmacol 401(2):191–195. https://doi.org/10.1016/S0014-2999(00)00428-3

    Article  PubMed  CAS  Google Scholar 

  25. Henniger MS, Wotjak CT, Holter SM (2003) Long-term voluntary ethanol drinking increases expression of NMDA receptor 2B subunits in rat frontal cortex. Eur J Pharmacol 470(1–2):33–36. https://doi.org/10.1016/S0014-2999(03)01787-4

    Article  PubMed  CAS  Google Scholar 

  26. Marutha Ravindran CR, Ticku MK (2004) Changes in methylation pattern of NMDA receptor NR2B gene in cortical neurons after chronic ethanol treatment in mice. Brain Res Mol Brain Res 121(1–2):19–27. https://doi.org/10.1016/j.molbrainres.2003.10.025

    Article  PubMed  CAS  Google Scholar 

  27. Marutha Ravindran CR, Ticku MK (2005) Role of CpG islands in the up-regulation of NMDA receptor NR2B gene expression following chronic ethanol treatment of cultured cortical neurons of mice. Neurochem Int 46(4):313–327. https://doi.org/10.1016/j.neuint.2004.10.004

    Article  PubMed  CAS  Google Scholar 

  28. Paul P, Dahale A, Kishore B, Chand P, Benegal V, Jain S, Murthy P, Purushottam M (2017) Association of N-methyl-D-aspartate receptor 2B subunit (GRIN2B) polymorphism with earlier age at onset of withdrawal symptoms in Indian alcohol dependent subjects. J Addict Dis 36(1):48–52. https://doi.org/10.1080/10550887.2016.1140434

    Article  PubMed  Google Scholar 

  29. Levran O, Peles E, Randesi M, Correa da Rosa J, Ott J, Rotrosen J, Adelson M, Kreek MJ (2016) Glutamatergic and GABAergic susceptibility loci for heroin and cocaine addiction in subjects of African and European ancestry. Prog Neuro-Psychopharmacol Biol Psychiatry 64:118–123. https://doi.org/10.1016/j.pnpbp.2015.08.003

    Article  CAS  Google Scholar 

  30. Kim JH, Park M, Yang SY, Jeong BS, Yoo HJ, Kim JW, Chung JH, Kim SA (2006) Association study of polymorphisms in N-methyl-D-aspartate receptor 2B subunits (GRIN2B) gene with Korean alcoholism. Neurosci Res 56(2):220–223. https://doi.org/10.1016/j.neures.2006.06.013

    Article  PubMed  CAS  Google Scholar 

  31. Vink JM, Smit AB, de Geus EJ, Sullivan P, Willemsen G, Hottenga JJ, Smit JH, Hoogendijk WJ et al (2009) Genome-wide association study of smoking initiation and current smoking. Am J Hum Genet 84(3):367–379. https://doi.org/10.1016/j.ajhg.2009.02.001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Xie P, Kranzler HR, Krystal JH, Farrer LA, Zhao H, Gelernter J (2014) Deep resequencing of 17 glutamate system genes identifies rare variants in DISC1 and GRIN2B affecting risk of opioid dependence. Addict Biol 19(5):955–964. https://doi.org/10.1111/adb.12072

    Article  PubMed  CAS  Google Scholar 

  33. Grucza RA, Johnson EO, Krueger RF, Breslau N, Saccone NL, Chen LS, Derringer J, Agrawal A et al (2010) Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genes. Addict Biol 15(3):346–357. https://doi.org/10.1111/j.1369-1600.2010.00220.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Levran O, Londono D, O'Hara K, Randesi M, Rotrosen J, Casadonte P, Linzy S, Ott J et al (2009) Heroin addiction in African Americans: a hypothesis-driven association study. Genes Brain Behav 8(5):531–540. https://doi.org/10.1111/j.1601-183X.2009.00501.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Zhao B, Zhu Y, Wang W, Cui HM, Wang YP, Lai JH (2013) Analysis of variations in the glutamate receptor, N-methyl D-aspartate 2A (GRIN2A) gene reveals their relative importance as genetic susceptibility factors for heroin addiction. PLoS One 8(8):e70817. https://doi.org/10.1371/journal.pone.0070817

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Tong G, Takahashi H, Tu S, Shin Y, Talantova M, Zago W, Xia P, Nie Z et al (2008) Modulation of NMDA receptor properties and synaptic transmission by the NR3A subunit in mouse hippocampal and cerebrocortical neurons. J Neurophysiol 99(1):122–132. https://doi.org/10.1152/jn.01044.2006

    Article  PubMed  CAS  Google Scholar 

  37. Roberts AC, Diez-Garcia J, Rodriguiz RM, Lopez IP, Lujan R, Martinez-Turrillas R, Pico E, Henson MA et al (2009) Downregulation of NR3A-containing NMDARs is required for synapse maturation and memory consolidation. Neuron 63(3):342–356. https://doi.org/10.1016/j.neuron.2009.06.016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Pachernegg S, Strutz-Seebohm N, Hollmann M (2012) GluN3 subunit-containing NMDA receptors: not just one-trick ponies. Trends Neurosci 35(4):240–249. https://doi.org/10.1016/j.tins.2011.11.010

    Article  PubMed  CAS  Google Scholar 

  39. Henson MA, Larsen RS, Lawson SN, Perez-Otano I, Nakanishi N, Lipton SA, Philpot BD (2012) Genetic deletion of NR3A accelerates glutamatergic synapse maturation. PLoS One 7(8):e42327. https://doi.org/10.1371/journal.pone.0042327

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Mohamad O, Song M, Wei L, SP Y (2013) Regulatory roles of the NMDA receptor GluN3A subunit in locomotion, pain perception and cognitive functions in adult mice. J Physiol 591(1):149–168. https://doi.org/10.1113/jphysiol.2012.239251

    Article  PubMed  CAS  Google Scholar 

  41. Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S et al (2002) Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415(6873):793–798. https://doi.org/10.1038/nature715

    Article  PubMed  CAS  Google Scholar 

  42. Xie XH, Liu HF, Zhang JB, Chen WS, Zhuang DD, Duan SW, Zhou WH (2016) Association between genetic variations of NMDA receptor NR3 subfamily genes and heroin addiction in male Han Chinese. Neurosci Lett 631:122–125. https://doi.org/10.1016/j.neulet.2016.08.025

    Article  PubMed  CAS  Google Scholar 

  43. Yang J, Wang S, Yang Z, Hodgkinson CA, Iarikova P, Ma JZ, Payne TJ, Goldman D et al (2015) The contribution of rare and common variants in 30 genes to risk nicotine dependence. Mol Psychiatry 20(11):1467–1478. https://doi.org/10.1038/mp.2014.156

    Article  PubMed  CAS  Google Scholar 

  44. Gelernter J (2015) Genetics of complex traits in psychiatry. Biol Psychiatry 77(1):36–42. https://doi.org/10.1016/j.biopsych.2014.08.005

    Article  PubMed  CAS  Google Scholar 

  45. Li MD (2008) Identifying susceptibility loci for nicotine dependence: 2008 update based on recent genome-wide linkage analyses. Hum Genet 123(2):119–131. https://doi.org/10.1007/s00439-008-0473-0

    Article  PubMed  CAS  Google Scholar 

  46. Bergen AW, Korczak JF, Weissbecker KA, Goldstein AM (1999) A genome-wide search for loci contributing to smoking and alcoholism. Genet Epidemiol 17(Suppl 1):S55–S60. https://doi.org/10.1002/gepi.1370170710

    Article  PubMed  Google Scholar 

  47. Li MD, Ma JZ, Cheng R, Dupont RT, Williams NJ, Crews KM, Payne TJ, Elston RC et al (2003) A genome-wide scan to identify loci for smoking rate in the Framingham Heart Study population. BMC Genet 4(Suppl 1):S103. https://doi.org/10.1186/1471-2156-4-S1-S103

    Article  PubMed  PubMed Central  Google Scholar 

  48. Gelernter J, Panhuysen C, Weiss R, Brady K, Poling J, Krauthammer M, Farrer L, Kranzler HR (2007) Genomewide linkage scan for nicotine dependence: identification of a chromosome 5 risk locus. Biol Psychiatry 61(1):119–126. https://doi.org/10.1016/j.biopsych.2006.08.023

    Article  PubMed  CAS  Google Scholar 

  49. Li MD (2006) The genetics of nicotine dependence. Curr Psychiatry Rep 8(2):158–164. https://doi.org/10.1007/s11920-006-0016-0

    Article  PubMed  CAS  Google Scholar 

  50. Ma JZ, Payne TJ, Nussbaum J, Li MD (2010) Significant association of glutamate receptor, ionotropic N-methyl-D-aspartate 3A (GRIN3A), with nicotine dependence in European- and African-American smokers. Hum Genet 127(5):503–512. https://doi.org/10.1007/s00439-010-0787-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Sham PC, Purcell SM (2014) Statistical power and significance testing in large-scale genetic studies. Nat Rev Genet 15(5):335–346. https://doi.org/10.1038/nrg3706

    Article  PubMed  CAS  Google Scholar 

  52. Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A (2010) Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res 20(1):110–121. https://doi.org/10.1101/gr.097857.109

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Takata A, Iwayama Y, Fukuo Y, Ikeda M, Okochi T, Maekawa M, Toyota T, Yamada K et al (2013) A population-specific uncommon variant in GRIN3A associated with schizophrenia. Biol Psychiatry 73(6):532–539. https://doi.org/10.1016/j.biopsych.2012.10.024

    Article  PubMed  CAS  Google Scholar 

  54. Wang F, Chen H, Steketee JD, Sharp BM (2007) Upregulation of ionotropic glutamate receptor subunits within specific mesocorticolimbic regions during chronic nicotine self-administration. Neuropsychopharmacol : Off Publ Am Coll Neuropsychopharmacol 32(1):103–109. https://doi.org/10.1038/sj.npp.1301033

    Article  CAS  Google Scholar 

  55. Nakajima A, Kinugasa Y, Torii J, Hishinuma T, Tomioka Y, Yamada K, Yamakuni T (2012) Repeated treatment with nicotine induces phosphorylation of NMDA receptor NR2B subunit in the brain regions involved in behavioral sensitization. Neurosci Lett 524(2):133–138. https://doi.org/10.1016/j.neulet.2012.07.022

    Article  PubMed  CAS  Google Scholar 

  56. Lovinger DM, White G, Weight FF (1989) Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243(4899):1721–1724. https://doi.org/10.1126/science.2467382

    Article  PubMed  CAS  Google Scholar 

  57. Lima-Landman MT, Albuquerque EX (1989) Ethanol potentiates and blocks NMDA-activated single-channel currents in rat hippocampal pyramidal cells. FEBS Lett 247(1):61–67. https://doi.org/10.1016/0014-5793(89)81241-4

    Article  PubMed  CAS  Google Scholar 

  58. Lovinger DM, White G, Weight FF (1990) NMDA receptor-mediated synaptic excitation selectively inhibited by ethanol in hippocampal slice from adult rat. J Neurosci: Off J Soc Neurosci 10(4):1372–1379

    Article  CAS  Google Scholar 

  59. Holmes A, Spanagel R, Krystal JH (2013) Glutamatergic targets for new alcohol medications. Psychopharmacology 229(3):539–554. https://doi.org/10.1007/s00213-013-3226-2

    Article  PubMed  CAS  Google Scholar 

  60. Gass JT, Olive MF (2008) Glutamatergic substrates of drug addiction and alcoholism. Biochem Pharmacol 75(1):218–265. https://doi.org/10.1016/j.bcp.2007.06.039

    Article  PubMed  CAS  Google Scholar 

  61. Vengeliene V, Bachteler D, Danysz W, Spanagel R (2005) The role of the NMDA receptor in alcohol relapse: a pharmacological mapping study using the alcohol deprivation effect. Neuropharmacology 48(6):822–829. https://doi.org/10.1016/j.neuropharm.2005.01.002

    Article  PubMed  CAS  Google Scholar 

  62. Vengeliene V, Bilbao A, Molander A, Spanagel R (2008) Neuropharmacology of alcohol addiction. Br J Pharmacol 154(2):299–315. https://doi.org/10.1038/bjp.2008.30

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Krishnan-Sarin S, O'Malley SS, Franco N, Cavallo DA, Morean M, Shi J, Pittman B, Krystal JH (2015) N-methyl-D-aspartate receptor antagonism has differential effects on alcohol craving and drinking in heavy drinkers. Alcohol Clin Exp Res 39(2):300–307. https://doi.org/10.1111/acer.12619

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Krystal JH, Petrakis IL, Mason G, Trevisan L, D'Souza DC (2003) N-methyl-D-aspartate glutamate receptors and alcoholism: reward, dependence, treatment, and vulnerability. Pharmacol Ther 99(1):79–94. https://doi.org/10.1016/S0163-7258(03)00054-8

    Article  PubMed  CAS  Google Scholar 

  65. Wernicke C, Samochowiec J, Schmidt LG, Winterer G, Smolka M, Kucharska-Mazur J, Horodnicki J, Gallinat J et al (2003) Polymorphisms in the N-methyl-D-aspartate receptor 1 and 2B subunits are associated with alcoholism-related traits. Biol Psychiatry 54(9):922–928. https://doi.org/10.1016/S0006-3223(03)00072-6

    Article  PubMed  CAS  Google Scholar 

  66. Paul P, Dahale A, Kishore B, Chand P, Benegal V, Jain S, Murthy P, Purushottam M (2016) Association of N-methyl-D-aspartate receptor 2B subunit (GRIN2B) polymorphism with earlier age at onset of withdrawal symptoms in Indian alcohol dependent subjects. J Addict Dis 36(1):1–5. https://doi.org/10.1080/10550887.2016.1140434

    Article  Google Scholar 

  67. Schumann G, Johann M, Frank J, Preuss U, Dahmen N, Laucht M, Rietschel M, Rujescu D et al (2008) Systematic analysis of glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior. Arch Gen Psychiatry 65(7):826–838. https://doi.org/10.1001/archpsyc.65.7.826

    Article  PubMed  CAS  Google Scholar 

  68. den Hartog CR, Gilstrap M, Eaton B, Lench DH, Mulholland PJ, Homanics GE, Woodward JJ (2017) Effects of repeated ethanol exposures on NMDA receptor expression and locomotor sensitization in mice expressing ethanol resistant NMDA receptors. Front Neurosci 11:84. https://doi.org/10.3389/fnins.2017.00084

    Article  Google Scholar 

  69. Xiang Y, Kim KY, Gelernter J, Park IH, Zhang H (2015) Ethanol upregulates NMDA receptor subunit gene expression in human embryonic stem cell-derived cortical neurons. PLoS One 10(8):e0134907. https://doi.org/10.1371/journal.pone.0134907

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Ridge JP, Ho AM, Innes DJ, Dodd PR (2008) The expression of NMDA receptor subunit mRNA in human chronic alcoholics. Ann N Y Acad Sci 1139(1):10–19. https://doi.org/10.1196/annals.1432.053

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Boehm SL 2nd, Peden L, Chang R, Harris RA, Blednov YA (2003) Deletion of the fyn-kinase gene alters behavioral sensitivity to ethanol. Alcohol Clin Exp Res 27(7):1033–1040. https://doi.org/10.1097/01.ALC.0000075822.80583.71

    Article  PubMed  CAS  Google Scholar 

  72. Zhao Y, Ren H, Dwyer DS, Peoples RW (2015) Different sites of alcohol action in the NMDA receptor GluN2A and GluN2B subunits. Neuropharmacology 97:240–250. https://doi.org/10.1016/j.neuropharm.2015.05.018

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Ronald KM, Mirshahi T, Woodward JJ (2001) Ethanol inhibition of N-methyl-D-aspartate receptors is reduced by site-directed mutagenesis of a transmembrane domain phenylalanine residue. J biol Chem 276(48):44729–44735. https://doi.org/10.1074/jbc.M102800200

    Article  PubMed  CAS  Google Scholar 

  74. Smothers CT, Woodward JJ (2006) Effects of amino acid substitutions in transmembrane domains of the NR1 subunit on the ethanol inhibition of recombinant N-methyl-D-aspartate receptors. Alcohol Clin Exp Res 30(3):523–530. https://doi.org/10.1111/j.1530-0277.2006.00058.x

    Article  PubMed  CAS  Google Scholar 

  75. den Hartog CR, Beckley JT, Smothers TC, Lench DH, Holseberg ZL, Fedarovich H, Gilstrap MJ, Homanics GE, Woodward JJ (2013) Alterations in ethanol-induced behaviors and consumption in knock-in mice expressing ethanol-resistant NMDA receptors Plos one 8 (11) e80541. DOI:https://doi.org/10.1371/journal.pone.0080541

  76. Honse Y, Ren H, Lipsky RH, Peoples RW (2004) Sites in the fourth membrane-associated domain regulate alcohol sensitivity of the NMDA receptor. Neuropharmacology 46(5):647–654. https://doi.org/10.1016/j.neuropharm.2003.11.006

    Article  PubMed  CAS  Google Scholar 

  77. Smothers CT, Woodward JJ (2016) Differential effects of TM4 tryptophan mutations on inhibition of N-methyl-d-aspartate receptors by ethanol and toluene. Alcohol 56:15–19. https://doi.org/10.1016/j.alcohol.2016.10.001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Gordey M, Mekmanee L, Mody I (2001) Altered effects of ethanol in NR2A(DeltaC/DeltaC) mice expressing C-terminally truncated NR2A subunit of NMDA receptor. Neuroscience 105(4):987–997. https://doi.org/10.1016/S0306-4522(01)00234-2

    Article  PubMed  CAS  Google Scholar 

  79. Xie X, Liu H, Zhang J, Chen W, Zhuang D, Duan S, Zhou W (2016) Association between genetic variations of NMDA receptor NR3 subfamily genes and heroin addiction in male Han Chinese. Neurosci Lett 631:122–125. https://doi.org/10.1016/j.neulet.2016.08.025

    Article  PubMed  CAS  Google Scholar 

  80. Itokawa M, Kasuga T, Yoshikawa T, Matsushita M (2004) Identification of a male schizophrenic patient carrying a de novo balanced translocation, t(4; 13)(p16.1; q21.31). Psychiatry Clin Neurosci 58(3):333–337. https://doi.org/10.1111/j.1440-1819.2004.01241.x

    Article  PubMed  Google Scholar 

  81. Zhong HJ, Huo ZH, Dang J, Chen J, Zhu YS, Liu JH (2014) Functional polymorphisms of the glutamate receptor N-methyl D-aspartate 2A gene are associated with heroin addiction. Genet Mol Res: GMR 13(4):8714–8721. https://doi.org/10.4238/2014.October.27.12

    Article  PubMed  CAS  Google Scholar 

  82. Itokawa M, Yamada K, Yoshitsugu K, Toyota T, Suga T, Ohba H, Watanabe A, Hattori E et al (2003) A microsatellite repeat in the promoter of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene suppresses transcriptional activity and correlates with chronic outcome in schizophrenia. Pharmacogenetics 13(5):271–278. https://doi.org/10.1097/01.fpc.0000054082.64000.63

    Article  PubMed  CAS  Google Scholar 

  83. Tang J, Chen X, Xu X, Wu R, Zhao J, Hu Z, Xia K (2006) Significant linkage and association between a functional (GT)n polymorphism in promoter of the N-methyl-D-aspartate receptor subunit gene (GRIN2A) and schizophrenia. Neurosci Lett 409(1):80–82. https://doi.org/10.1016/j.neulet.2006.09.022

    Article  PubMed  CAS  Google Scholar 

  84. Karler R, Calder LD, Chaudhry IA, Turkanis SA (1989) Blockade of “reverse tolerance” to cocaine and amphetamine by MK-801. Life Sci 45(7):599–606. https://doi.org/10.1016/0024-3205(89)90045-3

    Article  PubMed  CAS  Google Scholar 

  85. Dong Y, Saal D, Thomas M, Faust R, Bonci A, Robinson T, Malenka RC (2004) Cocaine-induced potentiation of synaptic strength in dopamine neurons: behavioral correlates in GluRA(−/−) mice. Proc Natl Acad Sci U S A 101(39):14282–14287. https://doi.org/10.1073/pnas.0401553101

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Bellone C, Luscher C (2006) Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nat Neurosci 9(5):636–641. https://doi.org/10.1038/nn1682

    Article  PubMed  CAS  Google Scholar 

  87. Yuan T, Mameli M, O'Connor EC, Dey PN, Verpelli C, Sala C, Perez-Otano I, Luscher C et al (2013) Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors. Neuron 80(4):1025–1038. https://doi.org/10.1016/j.neuron.2013.07.050

    Article  PubMed  CAS  Google Scholar 

  88. Ma JZ, Payne TJ, Li MD (2010) Significant association of glutamate receptor, ionotropic N-methyl-D-aspartate 3A (GRIN3A), with nicotine dependence in European- and African-American smokers. Hum Genet 127(5):503–512. https://doi.org/10.1007/s00439-010-0787-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Ma JZ, Payne TJ, Li MD (2010) Significant association of glutamate receptor, ionotropic N-methyl-d-aspartate 3A (GRIN3A), with nicotine dependence in European- and African-American smokers. Hum Genet 127(5):503–512. https://doi.org/10.1007/s00439-010-0787-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported in part by the China Precision Medicine Initiative (2016YFC0906300), Research Center for Air Pollution and Health of Zhejiang University, the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases of the First Affiliated Hospital of Zhejiang University, and National Institutes of Health grant DA012844. We thank Dr. David L. Bronson for excellent editing of this manuscript.

Author information

Authors and Affiliations

  1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, China

    Jiali Chen, Yunlong Ma, Rongli Fan, Zhongli Yang & Ming D. Li

  2. Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, China

    Ming D. Li

  3. Institute of NeuroImmune Pharmacology, Seton Hall University, South Orange, NJ, USA

    Ming D. Li

Authors
  1. Jiali Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yunlong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rongli Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhongli Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ming D. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhongli Yang or Ming D. Li.

Additional information

Dr. Ming D. Li is the first corresponding author.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, J., Ma, Y., Fan, R. et al. Implication of Genes for the N-Methyl-d-Aspartate (NMDA) Receptor in Substance Addictions. Mol Neurobiol 55, 7567–7578 (2018). https://doi.org/10.1007/s12035-018-0877-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-0877-3

Keywords

Search

Navigation