Advertisement

Journal of Neural Transmission

, Volume 126, Issue 2, pp 193–199 | Cite as

Effects of DRD2 splicing-regulatory polymorphism and DRD4 48 bp VNTR on crack cocaine addiction

  • Anderson R. Stolf
  • Renata B. Cupertino
  • Diana Müller
  • Breno Sanvicente-Vieira
  • Tatiana Roman
  • Eduardo S. Vitola
  • Eugenio H. Grevet
  • Lisia von Diemen
  • Felix H. P. Kessler
  • Rodrigo Grassi-Oliveira
  • Claiton H. D. Bau
  • Diego L. Rovaris
  • Flavio Pechansky
  • Jaqueline B. SchuchEmail author
Psychiatry and Preclinical Psychiatric Studies - Original Article
  • 108 Downloads

Abstract

There is evidence that dopamine receptors D2 (DRD2) and D4 (DRD4) polymorphisms may influence substance use disorders (SUD) susceptibility both individually and through their influence in the formation of DRD2–DRD4 heteromers. The dopaminergic role on the vulnerability to addiction appears to be influenced by sex. A cross-sectional study with 307 crack cocaine addicts and 770 controls was conducted. The influence of DRD2 rs2283265 and DRD4 48 bp VNTR in exon 3 variants, as well as their interaction on crack cocaine addiction susceptibility and severity were evaluated in women and men separately. An association between the DRD2 T allele and crack cocaine addiction was found in women. In this same group, interaction analysis demonstrated that the presence of DRD2-T allele and concomitant absence of DRD4-7R allele were associated with risk for crack cocaine addiction. No influence of DRD2 and DRD4 variants was observed in men regarding addiction severity. This study reinforces the role of dopaminergic genes in externalizing behaviors, especially the influence of DRD2–DRD4 interaction on SUD. This is the fourth sample that independently associated the DRD2–DRD4 interaction with SUD itself or related disorders. In addition, our findings point out to a potential difference of dopaminergic neurotransmission across sex influencing addiction susceptibility.

Keywords

Cocaine Crack Dependence Dopamine receptor D2 Dopamine receptor D4 Substance use disorder 

Notes

Acknowledgements

We are thankful to the staff of the participating psychiatric units for all their support with data collection.

Funding

This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq, 476529/2012-3, 466722/2014-1, and 466802/2014-5) and Secretaria Nacional de Políticas sobre Drogas (SENAD, 82264/2015). The funding sources had no involvement in study design; collection, analyses, and interpretation of data; in the writing of the report; in the decision to submit the article for publication.

Compliance with ethical standards

Conflict of interest

The author(s) declare the following potential conflict of interest with respect to the research, authorship, and/or publication of this article: Dr. Grevet was on the speaker’s bureau for Novartis and Shire for the last 3 years. He also received travel awards (air tickets and hotel accommodations) for participating in two psychiatric meetings from Shire and Novartis. All other authors reported no financial interests or potential conflicts of interest.

Supplementary material

702_2018_1946_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 15 KB)

References

  1. Abdalla RR, Madruga CS, Ribeiro M et al (2014) Prevalence of cocaine use in Brazil: data from the II Brazilian national alcohol and drugs survey (BNADS). Addict Behav 39:297–301.  https://doi.org/10.1016/j.addbeh.2013.10.019 CrossRefGoogle Scholar
  2. Alcantara AA, Chen V, Herring BE et al (2003) Localization of dopamine D2 receptors on cholinergic interneurons of the dorsal striatum and nucleus accumbens of the rat. Brain Res 986:22–29.  https://doi.org/10.1016/S0006-8993(03)03165-2 CrossRefGoogle Scholar
  3. Al-Eitan LN, Jaradat SA, Hulse GK, Tay GK (2012) Custom genotyping for substance addiction susceptibility genes in Jordanians of Arab descent. BMC Res Notes 5:497.  https://doi.org/10.1186/1756-0500-5-497 CrossRefGoogle Scholar
  4. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. DSM-IV, WashingtonGoogle Scholar
  5. Becker JB (1999) Gender differences in dopaminergic function in striatum and nucleus accumbens. Pharmacol Biochem Behav 64:803–812.  https://doi.org/10.1016/S0091-3057(99)00168-9 CrossRefGoogle Scholar
  6. Becker JB (2016) Sex differences in addiction. Dialogues Clin Neurosci 18:395–402.  https://doi.org/10.1016/B978-0-12-802114-9/00006-8 Google Scholar
  7. Becker JB, McClellan ML, Reed BG (2017) Sex differences, gender and addiction. J Neurosci Res 95:136–147.  https://doi.org/10.1002/jnr.23963 CrossRefGoogle Scholar
  8. Blasi G, Lo Bianco L, Taurisano P et al (2009) Functional variation of the dopamine D2 receptor gene is associated with emotional control as well as brain activity and connectivity during emotion processing in humans. J Neurosci 29:14812–14819.  https://doi.org/10.1523/JNEUROSCI.3609-09.2009 CrossRefGoogle Scholar
  9. Borroto-Escuela DO, Van Craenenbroeck K, Romero-Fernandez W et al (2011) Dopamine D2 and D4 receptor heteromerization and its allosteric receptor–receptor interactions. Biochem Biophys Res Commun 404:928–934.  https://doi.org/10.1016/j.bbrc.2010.12.083 CrossRefGoogle Scholar
  10. Bowman BP, Kuhn CM (1996) Age-related differences in the chronic and acute response to cocaine in the rat. Dev Psychobiol 29:597–611.  https://doi.org/10.1002/(SICI)1098-2302(199611)29:7%3C597::AID-DEV4%3E3.0.CO;2-P CrossRefGoogle Scholar
  11. Chen D, Liu F, Shang Q et al (2011) Association between polymorphisms of DRD2 and DRD4 and opioid dependence: evidence from the current studies. Am J Med Genet Part B Neuropsychiatr Genet 156:661–670.  https://doi.org/10.1002/ajmg.b.31208 CrossRefGoogle Scholar
  12. Chien C-C, Lin C-H, Chang Y-Y, Lung F-W (2010) Association of VNTR polymorphisms in the MAOA promoter and DRD4 exon 3 with heroin dependence in male Chinese addicts. World J Biol Psychiatry 11:409–416.  https://doi.org/10.3109/15622970903304459 CrossRefGoogle Scholar
  13. Das D, Tan X, Easteal S (2011) Effect of model choice in genetic association studies: DRD4 exon III VNTR and cigarette use in young adults. Am J Med Genet Part B Neuropsychiatr Genet 156:346–351.  https://doi.org/10.1002/ajmg.b.31169 CrossRefGoogle Scholar
  14. Dong G, Wang Z, Wang Y et al (2019) Gender-related functional connectivity and craving during gaming and immediate abstinence during a mandatory break: implications for development and progression of internet gaming disorder. Prog Neuropsychopharmacol Biol Psychiatry 88:1–10.  https://doi.org/10.1016/j.pnpbp.2018.04.009 CrossRefGoogle Scholar
  15. Duan J, Wainwright MS, Comeron JM et al (2003) Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 12:205–216CrossRefGoogle Scholar
  16. Fergusson DM, Boden JM, Horwood LJ (2008) The developmental antecedents of illicit drug use: evidence from a 25-year longitudinal study. Drug Alcohol Depend 96:165–177.  https://doi.org/10.1016/j.drugalcdep.2008.03.003 CrossRefGoogle Scholar
  17. First MB, Spitzer RL, Gibbon M, Williams JBW (2002) Structured clinical interview for DSM-IV-TR axis i disorders, Patient Edition (SCID-I/P, 11/2002 revision)Google Scholar
  18. Gardner EL (2011) Addiction and brain reward and antireward pathways. Chronic Pain Addict 30:22–69CrossRefGoogle Scholar
  19. Georgiou P, Zanos P, Bhat S et al (2018) Dopamine and stress system modulation of sex differences in decision making. Neuropsychopharmacology 43:313–324.  https://doi.org/10.1038/npp.2017.161 CrossRefGoogle Scholar
  20. Giros B, Sokoloff P, Martres MP et al (1989) Alternative splicing directs the expression of two D2 dopamine receptor isoforms. Nature 342:923–926.  https://doi.org/10.1038/342923a0 CrossRefGoogle Scholar
  21. González S, Rangel-barajas C, Peper M et al (2012) Dopamine D4 receptor, but not the ADHD-associated D4.7 variant, forms functional heteromers with the dopamine D2S receptor in the brain. Mol Psychiatry 17:650–662.  https://doi.org/10.1038/mp.2011.93.Dopamine CrossRefGoogle Scholar
  22. Haas AL, Peters RH (2000) Development of substance abuse problems among drug-involved offenders. Evidence for the telescoping effect. J Subst Abuse 12:241–253CrossRefGoogle Scholar
  23. Hardee JE, Cope LM, Munier EC et al (2017) Sex differences in the development of emotion circuitry in adolescents at risk for substance abuse: a longitudinal fMRI study. Soc Cogn Affect Neurosci 12:965–975.  https://doi.org/10.1093/scan/nsx021 CrossRefGoogle Scholar
  24. Harrell PT, Lin HY, Park JY et al (2016) Dopaminergic genetic variation moderates the effect of nicotine on cigarette reward. Psychopharmacology 233:351–360.  https://doi.org/10.1007/s00213-015-4116-6 CrossRefGoogle Scholar
  25. Henricks AM, Berger AL, Lugo JM et al (2017) Sex- and hormone-dependent alterations in alcohol withdrawal-induced anxiety and corticolimbic endocannabinoid signaling. Neuropharmacology 124:121–133.  https://doi.org/10.1016/j.neuropharm.2017.05.023 CrossRefGoogle Scholar
  26. Hogarth SJ, Jaehne EJ, van den Buuse M, Djouma E (2018) Brain-derived neurotrophic factor (BDNF) determines a sex difference in cue-conditioned alcohol seeking in rats. Behav Brain Res 339:73–78.  https://doi.org/10.1016/j.bbr.2017.11.019 CrossRefGoogle Scholar
  27. Hu M, Crombag HS, Robinson TE, Becker JB (2004) Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacology 29:81–85.  https://doi.org/10.1038/sj.npp.1300301 CrossRefGoogle Scholar
  28. Hulka LM, Eisenegger C, Preller KH et al (2014) Altered social and non-social decision-making in recreational and dependent cocaine users. Psychol Med 44:1015–1028.  https://doi.org/10.1017/S0033291713001839 CrossRefGoogle Scholar
  29. Hyer MM, Phillips LL, Neigh GN (2018) Sex differences in synaptic plasticity: hormones and beyond. Front Mol Neurosci 11:266.  https://doi.org/10.3389/fnmol.2018.00266 CrossRefGoogle Scholar
  30. Kellendonk C, Simpson EH, Polan HJ et al (2006) Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron 49:603–615.  https://doi.org/10.1016/j.neuron.2006.01.023 CrossRefGoogle Scholar
  31. Kessler F, Cacciola J, Alterman A et al (2012) Psychometric properties of the sixth version of the addiction severity index (ASI-6) in Brazil. Rev Bras Psiquiatr 34:24–33.  https://doi.org/10.1590/S1516-44462012000100006 CrossRefGoogle Scholar
  32. Knol MJ, VanderWeele TJ, Groenwold RHH et al (2011) Estimating measures of interaction on an additive scale for preventive exposures. Eur J Epidemiol 26:433–438.  https://doi.org/10.1007/s10654-011-9554-9 CrossRefGoogle Scholar
  33. Lahiri DK, Nurnberger JI (1991) A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP analysis. Nucleic Acids Res 19:5444.  https://doi.org/10.1093/nar/19.19.5444 CrossRefGoogle Scholar
  34. Lavalaye J, Booij J, Reneman L et al (2000) Effect of age and gender on dopamine transporter imaging with [123I]FP-CIT SPET in healthy volunteers. Eur J Nucl Med 27:867–869CrossRefGoogle Scholar
  35. Levran O, Peles E, Randesi M et al (2013) Association of genetic variation in pharmacodynamic factors with methadone dose required for effective treatment of opioid addiction. Pharmacogenomics 14:755–768.  https://doi.org/10.2217/pgs.13.58 CrossRefGoogle Scholar
  36. Levran O, Randesi M, da Rosa JC et al (2015) Overlapping dopaminergic pathway genetic susceptibility to heroin and cocaine addictions in African Americans. Ann Hum Genet 79:188–198.  https://doi.org/10.1111/ahg.12104 CrossRefGoogle Scholar
  37. Logrip ML, Oleata C, Roberto M (2017) Sex differences in responses of the basolateral-central amygdala circuit to alcohol, corticosterone and their interaction. Neuropharmacology 114:123–134.  https://doi.org/10.1016/j.neuropharm.2016.11.021 CrossRefGoogle Scholar
  38. Lynch WJ, Carroll ME (1999) Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology 144:77–82.  https://doi.org/10.1007/s002130050979 CrossRefGoogle Scholar
  39. Lynch WJ, Arizzi MN, Carroll ME (2000) Effects of sex and the estrous cycle on regulation of intravenously self-administered cocaine in rats. Psychopharmacology 152:132–139.  https://doi.org/10.1007/s002130000488 CrossRefGoogle Scholar
  40. Mallard TT, Doorley J, Esposito-Smythers CL, McGeary JE (2016) Dopamine D4 receptor VNTR polymorphism associated with greater risk for substance abuse among adolescents with disruptive behavior disorders: preliminary results. Am J Addict 25:56–61CrossRefGoogle Scholar
  41. Mbarek H, Milaneschi Y, Fedko IO et al (2015) The genetics of alcohol dependence: twin and SNP-based heritability, and genome-wide association study based on AUDIT scores. Am J Med Genet Part B Neuropsychiatr Genet 168:739–748.  https://doi.org/10.1002/ajmg.b.32379 CrossRefGoogle Scholar
  42. McCarthy MM, Arnold AP, Ball GF et al (2012) Sex differences in the brain: the not so inconvenient truth. J Neurosci 32:2241–2247.  https://doi.org/10.1523/JNEUROSCI.5372-11.2012 CrossRefGoogle Scholar
  43. McGeary J (2009) The DRD4 exon 3 VNTR polymorphism and addiction-related phenotypes: a review. Pharmacol Biochem Behav 93:222–229.  https://doi.org/10.1016/j.pbb.2009.03.010 CrossRefGoogle Scholar
  44. Mosher Ruiz S, Oscar-Berman M, Kemppainen MI et al (2017) associations between personality and drinking motives among abstinent adult alcoholic men and women. Alcohol Alcohol 52:496–505.  https://doi.org/10.1093/alcalc/agx016 CrossRefGoogle Scholar
  45. Mota NR, Bau CHD, Banaschewski T et al (2013a) Association between DRD2/DRD4 interaction and conduct disorder: a potential developmental pathway to alcohol dependence. Am J Med Genet Part B Neuropsychiatr Genet 162:546–549.  https://doi.org/10.1002/ajmg.b.32179 CrossRefGoogle Scholar
  46. Mota NR, Rovaris DL, Bertuzzi GP et al (2013b) DRD2/DRD4 heteromerization may influence genetic susceptibility to alcohol dependence. Mol Psychiatry 18:401–402.  https://doi.org/10.1038/mp.2012.50 CrossRefGoogle Scholar
  47. Moyer RA, Wang D, Papp AC et al (2011) Intronic polymorphisms affecting alternative splicing of human dopamine D2 receptor are associated with cocaine abuse. Neuropsychopharmacology 36:753–762.  https://doi.org/10.1038/npp.2010.208 CrossRefGoogle Scholar
  48. Mozley LH, Gur RC, Mozley PD, Gur RE (2001) Striatal Dopamine transporters and cognitive functioning in healthy men and women. Am J Psychiatry 158:1492–1499.  https://doi.org/10.1176/appi.ajp.158.9.1492 CrossRefGoogle Scholar
  49. Patriquin MA, Bauer IE, Soares JC et al (2015) Addiction pharmacogenetics: a systematic review of the genetic variation of the dopaminergic system. Psychiatr Genet 25:181–193.  https://doi.org/10.1097/YPG.0000000000000095 CrossRefGoogle Scholar
  50. Pope SK, Falck RS, Carlson RG et al (2011) Characteristics of rural crack and powder cocaine use: gender and other correlates. Am J Drug Alcohol Abuse 37:491–496.  https://doi.org/10.3109/00952990.2011.600380 CrossRefGoogle Scholar
  51. Primus RJ, Thurkauf A, Xu J et al (1997) Localization and characterization of dopamine D4 binding sites in rat and human brain by use of the novel, D4 receptor-selective ligand [3H]NGD 94-1.2. J Pharmacol Exp Ther 282:1020–1027Google Scholar
  52. Ratnu VS, Emami MR, Bredy TW (2017) Genetic and epigenetic factors underlying sex differences in the regulation of gene expression in the brain. J Neurosci Res 95:301–310.  https://doi.org/10.1002/jnr.23886 CrossRefGoogle Scholar
  53. Sawyer KS, Oscar-Berman M, Barthelemy OJ et al (2017) Gender dimorphism of brain reward system volumes in alcoholism. Psychiatry Res Neuroimaging 263:15–25.  https://doi.org/10.1016/j.pscychresns.2017.03.001 CrossRefGoogle Scholar
  54. Spellicy CJ, Kosten TR, Hamon SC et al (2013) ANKK1 and DRD2 pharmacogenetics of disulfiram treatment for cocaine abuse. Pharmacogenet Genomics 23:333–340.  https://doi.org/10.1097/FPC.0b013e328361c39d CrossRefGoogle Scholar
  55. Staley JK, Krishnan-Sarin S, Zoghbi S et al (2001) Sex differences in [123I]beta-CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and nonsmokers. Synapse 41:275–284.  https://doi.org/10.1002/syn.1084 CrossRefGoogle Scholar
  56. Stringer S, Minică CC, Verweij KJH et al (2016) Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium. Transl Psychiatry 6:e769.  https://doi.org/10.1038/tp.2016.36 CrossRefGoogle Scholar
  57. Sullivan D, Pinsonneault JK, Papp AC et al (2013) Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene-gene-environment interaction. Transl Psychiatry 3:e222–e228.  https://doi.org/10.1038/tp.2012.146 CrossRefGoogle Scholar
  58. Vernaglia TVC, Leite TH, Faller S et al (2017) The female crack users: Higher rates of social vulnerability in Brazil. Health Care Women Int 38:1170–1187.  https://doi.org/10.1080/07399332.2017.1367001 CrossRefGoogle Scholar
  59. Walker QD, Cabassa J, Kaplan KA et al (2001a) Sex differences in cocaine-stimulated motor behavior: disparate effects of gonadectomy. Neuropsychopharmacology 25:118–130.  https://doi.org/10.1016/S0893-133X(00)00248-7 CrossRefGoogle Scholar
  60. Walker QD, Francis R, Cabassa J, Kuhn CM (2001b) Effect of ovarian hormones and estrous cycle on stimulation of the hypothalamo-pituitary–adrenal axis by cocaine. J Pharmacol Exp Ther 297:291–298Google Scholar
  61. Walker QD, Ray R, Kuhn CM (2006) Sex differences in neurochemical effects of dopaminergic drugs in rat striatum. Neuropsychopharmacology 31:1193–1202.  https://doi.org/10.1038/sj.npp.1300915 CrossRefGoogle Scholar
  62. Ward RD, Kellendonk C, Simpson EH et al (2010) Impaired timing precision produced by striatal D2 receptor overexpression is mediated by cognitive and motivational deficits. Behav Neurosci 123:720–730.  https://doi.org/10.1037/a0016503.Impaired CrossRefGoogle Scholar
  63. Xu X, Clark US, David SP et al (2014) The effects of nicotine deprivation and replacement on BOLD-fMRI response to smoking cues as a function of DRD4 VNTR genotype. Nicotine Tob Res 16:939–947.  https://doi.org/10.1093/ntr/ntu010 CrossRefGoogle Scholar
  64. Zaidi ZF (2010) Gender differences in human brain: a review. Open Anat J 2:37–55.  https://doi.org/10.2174/1877609401002010037 CrossRefGoogle Scholar
  65. Zhang Y, Bertolino A, Fazio L et al (2007) Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc Natl Acad Sci USA 104:20552–20557.  https://doi.org/10.1073/pnas.0707106104 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  • Anderson R. Stolf
    • 1
  • Renata B. Cupertino
    • 2
  • Diana Müller
    • 2
  • Breno Sanvicente-Vieira
    • 3
  • Tatiana Roman
    • 2
  • Eduardo S. Vitola
    • 4
  • Eugenio H. Grevet
    • 4
  • Lisia von Diemen
    • 1
  • Felix H. P. Kessler
    • 1
  • Rodrigo Grassi-Oliveira
    • 3
  • Claiton H. D. Bau
    • 1
    • 4
  • Diego L. Rovaris
    • 2
  • Flavio Pechansky
    • 1
  • Jaqueline B. Schuch
    • 2
    • 5
    Email author
  1. 1.Center for Drug and Alcohol Research, Hospital de Clínicas de Porto AlegreUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Department of Genetics, Instituto de BiociênciasUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  3. 3.Developmental Cognitive Neuroscience Lab (DCNL)Pontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil
  4. 4.ADHD Outpatient Program, Adult DivisionHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  5. 5.Laboratory of Immunosenescence, Graduate Program in Biomedical GerontologyPontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil

Personalised recommendations