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Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: a review

Published online by Cambridge University Press:  16 April 2020

E.P. Noble
E.P. Noble*
Affiliation:
Department of Psychiatry and Biobehavioral Sciences, and the Brain Research Institute, University of California, Los AngelesCA, USA
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Summary

Since 1990, association studies have amassed strong evidence implicating the D2 dopamine receptor (DRD2) gene in alcoholism. Specifically, the Taql A minor (A1) allele of the DRD2 gene has been associated with alcoholism. The DRD2 gene has also been found to be involved in other substance use disorders including cocaine, nicotine and opioid dependence, and obesity. Beyond association studies, pharmacologic studies have shown reduced brain D2 dopamine receptor numbers in A1+ allele carriers (A1A1 and A1A2 genotypes) compared to A1– allele carriers (A2A2 genotype). Through a number of other approaches, different phenotypes have also been identified in subjects with the A1+ and A1– alleles. These include metabolic, neurophysiological, neuropsychological, personality, stress and treatment studies. It is hypothesized that in an effort to compensate for deficiencies in the dopaminergic system, substance abusers may seek to stimulate the mesocorticolimbic circuits of the brain, long thought to be important in behavioral reward and reinforcement. In effect, one form of the DRD2 gene, the A1 allele, renders the dopaminergic system inefficient and rewards substance abuse that increases brain dopamine levels.

Keywords

alcoholismdopamineDRD2 genedrugsnicotineobesity
Type
Review
Information
European Psychiatry , Volume 15 , Issue 2 , March 2000 , pp. 79 - 89
Copyright
Copyright © Éditions scientifiques et médicales Elsevier SAS 2000

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References

Adams, K.MGilman, SKoeppe, R.AKluin, K.JBrunberg, J.ADede, D et al. Neuropsychological deficits are correlated with frontal hypometabolism in positron emission tomography studies of older alcoholic patients. Alcohol Clin Exp Res 17 1993 205–210CrossRefGoogle ScholarPubMed
Amadéo, SAbbar, MFourcade, M.LWaksman, GLeroux, M.GMedec, A et al. D2 dopamine receptor gene and alcoholism. J Psychiatr Res 27 1993 173–179CrossRefGoogle ScholarPubMed
Babor, T.FHofmann, MDelBoca, F.KHesselbrock, VMeyer, R.EDolinsky, Z.S et al. Types of alcoholics: I. Evidence for an empirically derived typology based on indicators of vulnerability and severity. Arch Gen Psychiatry 49 1992 599–608CrossRefGoogle ScholarPubMed
Benjamin, JLi, LPatterson, CGreenberg, B.DMurphy, D.LHamer, D.HPopulation and familial association between the D4 dopamine receptor gene and measures of novelty seeking. Nat Genet 12 1996 81–8410.1038/ng0196-81CrossRefGoogle ScholarPubMed
Berman, S.MNoble, E.PReduced visuospatial performance in children with the D2 dopamine receptor A1 allele. Behav Genet 25 1995 45–58CrossRefGoogle ScholarPubMed
Berman, S.MNoble, E.PThe D2 dopamine receptor (DRD2) gene and family stress. Interactive effects on cognitive functioning in children. Behav Genet 27 1997 33–4310.1023/A:1025611208475CrossRefGoogle ScholarPubMed
Blum, KBraverman, E.PDinardo, M.JWood, R.CSheridan, P.JProlonged P300 latency in a neuropsychiatric population with the D2 dopamine receptor A1 allele. Pharmacogenetics 3 1994 313–322CrossRefGoogle Scholar
Blum, KNoble, E.PSheridan, P.JFinley, OMontgomery, ARitchie, T et al. Association of the A1 allele of the human D2 dopamine receptor gene with severe alcoholism. Alcohol 8 1991 409–416CrossRefGoogle ScholarPubMed
Blum, KNoble, E.PSheridan, P.JMontgomery, ARitchie, TJagadeeswaran, P et al. Allelic association of human dopamine D2 receptor gene in alcoholism. JAMA 263 1990 2055–2060CrossRefGoogle ScholarPubMed
Blum, KSheridan, P.JWood, R.CBraverman, E.RChen, I.J.HComings, D.EDopamine D2 receptor gene variants: Association and linkage studies in impulsive-addictive-compulsive behavior. Pharmacogenetics 5 1995 121–141CrossRefGoogle Scholar
Bolos, A.MDean, MLucase-Derse, SRamsburg, MBrown, G.LGoldman, D et al. Population and pedigree studies reveal a lack of association between the dopamine D2 receptor gene and alcoholism. JAMA 264 1990 3156–316010.1001/jama.1990.03450240058040CrossRefGoogle ScholarPubMed
Cloninger, C.RNeurogenetic adaptive mechanisms in alcoholism. Science 236 1987 410–416CrossRefGoogle ScholarPubMed
Cloninger, C.RD2 dopamine receptor gene is associated but not linked with alcoholism. JAMA 266 1991 1833–1834CrossRefGoogle Scholar
Comings, D.EComings, B.GMuhleman, DDietz, GShahbahrami, BTast, D et al. The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. JAMA 266 1991 1793–1800CrossRefGoogle ScholarPubMed
Comings, D.EFerry, LBradshaw-Robinson, SBurchette, RChiu, CMuhleman, DThe dopamine D2 receptor (DRD2) gene: A genetic risk factor in smoking. Pharmacogenetics 6 1996 73–79CrossRefGoogle ScholarPubMed
Comings, D.EFlanagan, S.DDietz, GMuhleman, DKnell, EGysin, RThe dopamine D2 receptor (DRD2) as a major gene in obesity and height. Biochem Med Metab Biol 50 1993 176–18510.1006/bmmb.1993.1059CrossRefGoogle ScholarPubMed
Comings, D.EGade, RMacmurray, J.PMuhleman, DPeters, W.RGenetic variants of the human obesity (OB) gene: association with body mass index in young women, psychiatric symptoms, and interaction with the dopamine D2 receptor (DRD2) gene. Mol Psychiatry 1 1996 325–335Google ScholarPubMed
Comings, D.EMuhleman, DAhn, CGysin, RFlanagan, S.DThe dopamine D2 receptor gene: A genetic risk factor in substance abuse. Drug Alcohol Depend 34 1994 175–180CrossRefGoogle ScholarPubMed
Cook, B.LWang, Z.WCrowe, R.RHauser, RFreimer, MAlcoholism and the D2 receptor gene. Alcohol Clin Exp Res 16 1992 806–809CrossRefGoogle ScholarPubMed
Cook, C.C.HGurling, H.M.DThe D2 dopamine receptor gene and alcoholism: A genetic effect on the liability for alcoholism. J R Soc M 87 1994 400–402Google ScholarPubMed
Ebstein, R.PNovick, OUmansky, RPriel, BOsher, YBlaine, D et al. Dopamine D4 receptor (DRD4) exon III polymorphism associated with the human personality trait of novelty seeking. Nat Genet 12 1996 78–8010.1038/ng0196-78CrossRefGoogle ScholarPubMed
Gabbay, F.HDuncan, C.CBird, GUhl, G.RMirsky, A.FD2 dopamine receptor Taq1 A genotypic differences in event-related brain potentials.Harris, L.SProblems of Drug Dependence. NIDA Research Monograph 162. 129 1996 Rockville MD, NIH, National Institute of Drug AbuseGoogle Scholar
Gehle, V.MErwin, V.GCommon quantitative trait loci for alcohol-related behaviors and CNS neurotensin measures: voluntary ethanol consumption. Alcohol Clin Exp Res 22 1998 40–48Google ScholarPubMed
Geijer, TNeiman, JRydberg, UGyllander, AJöhnson, ESedvall, G et al. Dopamine D2 receptor gene polymorphisms in Scandinavian chronic alcoholics. Eur Arch Psychiatry Clin Neursci 244 1994 26–32CrossRefGoogle ScholarPubMed
Gelernter, JGoldman, DRisch, NThe A1 allele of the D2 dopamine receptor gene and alcoholism. JAMA 269 1993 1673–1677CrossRefGoogle ScholarPubMed
Gelernter, JO'Malley, SRisch, NKranzler, H.RKrystal, JMerikangas, K et al. No association between an allele of the D2 dopamine receptor gene (DRD2) and alcoholism. JAMA 266 1991 1801–1807CrossRefGoogle ScholarPubMed
Goldman, DDean, MBrown, G.LBolos, A.NTokola, RVirkkunen, M et al. D2 dopamine receptor genotype and cerebral spinal fluid homovanillic acid, 5-hydroxyindoleacetic acid and 3-methoxy-4-hydroxyphenylglycol in alcoholics in Finland and the United States. Acta Psychiatr Scand 86 1992 351–357CrossRefGoogle ScholarPubMed
Gorwood, PAdes, JFeingold, JAre genes coding for dopamine receptors implicated in alcoholism? Eur Psychiatry 9 1994 63–69CrossRefGoogle Scholar
Grandy, D.KLitt, MAllen, LBunzow, J.RMarchionni, MMakam, H et al. The human dopamine D2 receptor gene is located on chromosome 11 at q22-q23 and identifies a Taq1 RFLP. Am J Hum Genet 45 1989 778–785Google Scholar
Heinz, ASander, THarms, HFinckh, UKuhn, SDufeu, P et al. Lack of allelic association of dopamine D1 and D2 (TaqI A) receptor gene polymorphisms with reduced dopaminergic sensitivity in alcoholism. Alcohol Clin Exp Res 20 1996 1109–1113CrossRefGoogle Scholar
Hietala, JPohjalainen, THeikkila-Kallio, UWest, CSalaspuro, MSyvälahti, EAllelic association between D2 but not D1 dopamine receptor gene and alcoholism in Finland. Psychiat Genet 7 1997 19–25CrossRefGoogle Scholar
Hill, S.YLocke, JZezza, NKaplan, BNeiswanger, KSteinhauer, S.R et al. Genetic association between reduced P300 amplitude and the DRD2 dopamine receptor A1 allele in children at high-risk for alcoholism. Biol Psychiatry 43 1998 40–51CrossRefGoogle ScholarPubMed
Hitzemann, R.JThe regulation of D2 dopamine receptor expression. Mol Psychiatry 3 1998 198–20310.1038/sj.mp.4000388CrossRefGoogle ScholarPubMed
Jönsson, E.GNöthen, M.MGustavsson, J.PNeidt, HBrené, STylee, A et al. Lack of evidence for allelic association between personality traits and dopamine D4 receptor gene polymorphism. Am J Psychiatry 154 1997 697–699Google Scholar
Koob, G.RDrugs of abuse. Anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 13 1992 177–184CrossRefGoogle ScholarPubMed
Laruelle, MGelernter, JInnis, R.BD2 receptors binding potential is not affected by Taq1 polymorphism at the D2 receptor gene. Mol Psychiatry 3 1998 261–265CrossRefGoogle Scholar
Lawford, B.RYoung, R.MRowell, J.AGibson, J.NFeeney, G.F.XRitchie, T.L et al. Association of the D2 dopamine receptor A1 allele with alcoholism: Medical severity of alcoholism and type of controls. Biol Psychiatry 41 1997 386–393CrossRefGoogle ScholarPubMed
Lawford, B.RYoung, R.MRowell, J.AQualichefski, JFletcher, B.HSyndulko, K et al. Bromocriptine in the treatment of alcoholics with the D2 dopamine receptor A1 allele. Nat M 1 1995 337–341CrossRefGoogle ScholarPubMed
Maldonado, RSalardi, AValverde, OSamad, T.ARoques, B.PBorrelli, EAbsence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature 388 1997 586–589CrossRefGoogle ScholarPubMed
Malhotra, A.KVirkunnen, MRooney, WEggert, MLinnoila, MGoldman, DThe association between the dopamine D4 receptor (DRD4) 16 amino acid repeat polymorphism and novelty seeking. Mol Psychiatry 1 1996 388–391Google ScholarPubMed
Neiswanger, KHill, S.YKaplan, B.BAssociation and linkage studies of the TaqI A allele of the dopamine D2 receptor gene in samples of female and male alcoholics. Am J Med Genet 60 1995 267–271CrossRefGoogle Scholar
Noble, E.PAlcoholism and the dopaminergic system: A review. Addict Biol 1 1996 333–348CrossRefGoogle ScholarPubMed
Noble, E.PThe D2 dopamine receptor gene: A review of association studies in alcoholism and phenotypes. Alcohol 16 1998 33–45CrossRefGoogle ScholarPubMed
Noble, E.PThe DRD2 gene, smoking, and lung cancer. J Natl Cancer Inst 90 1998 343–345CrossRefGoogle ScholarPubMed
Noble, E.PBerman, S.MOzkaragoz, T.ZRitchie, TProlonged P300 latency in children with the D2 dopamine receptor A1 allele. Am J Hum Genet 54 1994 658–668Google ScholarPubMed
Noble, E.PBlum, KAlcoholism and the D2 receptor gene [letter]. JAMA 270 1993 1547CrossRefGoogle Scholar
Noble, E.PBlum, KKhalsa, M.ERitchie, TMontgomery, AWood, R.D et al. Allelic association of the D2 dopamine receptor gene with cocaine dependence. Drug Alcohol Depend 33 1993 271–285CrossRefGoogle ScholarPubMed
Noble, E.PBlum, KRitchie, TMontgomery, ASheridan, P.JAllelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism. Arch Gen Psychiatry 48 1991 648–654CrossRefGoogle ScholarPubMed
Noble, E.PFitch, R.JRitchie, TBrunner, R.LZhang, XStjeor, S.C et al. The D2 dopamine receptor gene: obesity, smoking and mood.St. Jeor, S.TObesity Assessment. 1997 Chapman and Hall; New York522–533Google Scholar
Noble, E.PGottschalk, L.AFallon, J.HRitchie, T.LWu, J.CD2 dopamine receptor polymorphism and brain regional metabolism. Am J Med Genet 74 1997 162–1663.0.CO;2-W>CrossRefGoogle Scholar
Noble, E.PLawford, B.RRitchie, TYoung, R.MZhang, XThe D2 dopamine receptor (DRD2) gene and methadone treatment outcome of opioid-dependent patients. Abstr Soc. Neurosci 24 1998 770Google Scholar
Noble, E.PNoble, R.ERitchie, TSyndulko, KBohlman, M.CNoble, L.A et al. D2 dopamine receptor gene and obesity. Int J Eating Disord 15 1994 205–2173.0.CO;2-P>CrossRefGoogle ScholarPubMed
Noble, E.POzkaragoz, T.ZRitchie, TZhang, XBelin, T.RSparkes, R.SD2 and D4 dopamine receptor polymorphisms and personality. Am J Med Genet 81 1998 257–2673.0.CO;2-E>CrossRefGoogle Scholar
Noble, E.PStjeor, S.TRitchie, TSyndulko, KStjeor, S.CFitch, R.J et al. D2 dopamine receptor gene and cigarette smoking: A reward gene? Med Hypotheses 42 1994 257–260CrossRefGoogle ScholarPubMed
Noble, E.PSyndulko, KFitch, R.JRitchie, TBohlman, M.CGuth, P et al. TaqI A alleles in medically ill alcoholic and nonalcoholic patients. Alcohol Alcohol 29 1994 729–744Google Scholar
O'Hara, B.FSmith, S.SBird, GPersico, A.MSuarez, B.KCutting, G.R et al. Dopamine D2 receptor RFLPs, haplotypes and their association with substance use in black and Caucasian research volunteers. Hum Her 43 1993 209–218CrossRefGoogle ScholarPubMed
Parsian, ATodd, R.DDevor, E.JO'Malley, K.LSuarez, B.KReich, T et al. Alcoholism and alleles of the human D2 receptor locus: Studies of association and linkage. Arch Gen Psychiatry 48 1991 655–663CrossRefGoogle ScholarPubMed
Pato, C.NMacciardi, FPato, M.TVerga, MKennedy, HReview of the putative association of dopamine D2 receptor and alcoholism: A meta-analysis. Am J Med Genet 48 1993 78–82CrossRefGoogle ScholarPubMed
Persico, A.MBird, GGabbay, F.HUhl, G.RD2 dopamine receptor gene TaqI A1 and B1 restriction fragment length polymorphism: Enhanced frequencies in psychostimulant-preferring polysubstance abusers. Biol Psychiatry 40 1996 776–784CrossRefGoogle ScholarPubMed
Phillips, T.JBrown, K.JBurkhart-Kasch, SWenger, C.DKelly, M.ARubinstein, M et al. Alcohol preference and sensitivity are markedly reduced in mice lacking dopamine D2 receptors. Nat Neurosci 1 1998 610–615CrossRefGoogle ScholarPubMed
Phillips, T.JCrabbe, J.CMetten, PBelknap, J.KLocalization of genes affecting alcohol drinking in mice. Alcohol Clin Exp Res 18 1994 931–943CrossRefGoogle ScholarPubMed
Phillips, T.JHuson, MGwazdon, CBurkhart-Kasch, SShen, E.HEffects of acute and repeated ethanol exposures on the locomotor activity of RXD recombinant inbred mice. Alcohol Clin Exp Res 19 1995 269–278CrossRefGoogle Scholar
Pohjalainen, TRinne, J.ONågren, KLehikoinen, PAnttila, KSyvälahti, E.K.G et al. The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry 3 1998 256–260CrossRefGoogle ScholarPubMed
Smith, S.SO'Hara, B.FPersico, A.MGorelick, D.ANewlin, D.BVlahov, D et al. Genetic vulnerability in drug abuse: The dopamine D2 receptor TaqI B RFLP is more frequent in polysubstance abusers. Arch Gen Psychiatry 49 1992 723–727CrossRefGoogle Scholar
Spitz, M.RShi, HYang, FHudmon, K.SJiang, HChamberlain, R.M et al. Case-control study of the D2 dopamine receptor gene and smoking status in lung cancer patients. J Natl Cancer Inst 90 1998 358–363CrossRefGoogle ScholarPubMed
Suarez, B.KParsian, AHampe, C.LTodd, R.DReich, TCloninger, C.RLinkage disequilibria and the D2 dopamine receptor locus (DRD2) in alcoholics and controls. Genomics 19 1994 12–20CrossRefGoogle ScholarPubMed
Tarantino, L.MMcClearn, G.ERodriguez, L.APlomin, RConfirmation of quantitative trait loci for alcohol preference in mice. Alcohol Clin Exp Res 22 1998 1099–1105CrossRefGoogle ScholarPubMed
Thompson, JThomas, NSingleton, APiggott, MLloyd, SPerry, C.M et al. D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics 7 1997 479–484CrossRefGoogle ScholarPubMed
Turner, EEwing, JShilling, PSmith, T.LIrwin, MSchuckit, M et al. Lack of association between an RFLP near the D2 dopamine receptor gene and severe alcoholism. Biol Psychiatry 31 1992 285–290CrossRefGoogle ScholarPubMed
Uhl, GBlum, KNoble, ESmith, SSubstance abuse vulnerability and D2 receptor gene. Trends Neurosci 16 1993 83–88CrossRefGoogle Scholar
Volkow, N.DFowler, J.BWang, G.JHitzemann, RLogan, JSchyler, D.J et al. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 14 1993 169–177CrossRefGoogle ScholarPubMed
Volkow, N.DHitzemann, RWang, G.JFowler, J.SWolf, A.PDewey, S.L et al. Long-term frontal brain metabolism changes in cocaine abusers. Synapse 11 1992 184–190CrossRefGoogle ScholarPubMed
Wik, GBorg, SSjögren, IWiesel, F.ABloomquist, GBorg, J et al. PET determination of regional cerebral glucose metabolism in alcohol-dependent men and healthy controls using 11C-glucose. Acta Psychiatr Scand 78 1988 234–241CrossRefGoogle ScholarPubMed
Wise, R.ARompre, P.PBrain dopamine and reward. Annu Rev Psychol 40 1989 191–225CrossRefGoogle ScholarPubMed
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