Variation in the DRD2 gene affects impulsivity in intertemporal choice

Yoshiya Kawamura, Taiki Takahashi, Xiaoxi Liu, Nao Nishida, Yoshihiro Noda, Akane Yoshikawa, Tadashi Umekage, Tsukasa Sasaki

Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada&Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Department of Behavioral Science, Graduate School of Letters, Hokkaido University, Sapporo, Japan.
Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan&Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Department of Physical and Health Education, Graduate School of Education, University of Tokyo, Tokyo, Japan.
Department of Psychiatry, Sakae Seijinkai Hospital, Yokohama, Japan.
Division for Environment, Health and Safety, University of Tokyo, Tokyo, Japan.

DOI: 10.4236/ojpsych.2013.31005                

Abstract

Introduction: Impulsivity in intertemporal choice has been operationalized as “delay discounting,” referring to the preference for a sooner, smaller reward in neuroeconomics. It is reportedly associated with the dopaminergic systems. Dopamine receptor D2 (DRD2) is the D2 subtype of the dopamine receptor of the G-protein coupled receptor family. The aim of this study was to explore the effect of single nucleotide polymorphisms (SNPs) in DRD2 gene on delay discounting. Methods: The participants consisted of 91 healthy Japanese people (66 males and 25 females with a mean age of 40.9 ± 6.9 years). Each participant completed the Kirby’s monetary choice questionnaire (MCQ) for delayed gain and donated a whole blood sample. Two SNPs (C957T (rs6277) and TaqI A (rs1800497)) in DRD2 were genotyped by using the DigiTag2 assay. SNP linear regression analyses with 100,000 permutations were conducted for the hyperbolic time-discount rate (k). Results: The SNP C957T showed a significant association; participants with more minor alleles (T) were more impulsive in intertemporal choice for delayed gain (multiplicity-corrected P = 0.041 with a small effect size). Conclusion: The variation in the DRD2 gene is associated with impulsive decision-making. This is the first study to demonstrate an association between DRD2 and impulsivity in intertemporal choice with a multiplicity-corrected significance.

Keywords

Dopamine receptor D2 (DRD2); Impulsivity; Neuroeconomics; Single Nucleotide Polymorphism (SNP); Time-Discount Rate

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Glimcher, P.W. and Rustichini, A. (2004) Neuroeconomics: The consilience of brain and decision. Science, 306, 447-452. doi:10.1126/science.1102566
[2]	Camerer, C., Loewenstein, G.F. and Prelec D. (2005) Neuroeconomics: How neuroscience can inform economics. Journal of Economic Literature, 43, 9-64. doi:10.1257/0022051053737843
[3]	Takahashi, T. (2009) Theoretical frameworks for neuroeconomics of intertemporal choice. Journal of Neuroscience, Psychology, and Economics, 2, 75-90. doi:10.1037/a0015463
[4]	Hasler, G. (2012) Can the neuroeconomics revolution revolutionize psychiatry? Neuroscience and Biobehavioral Reviews, 36, 64-78. doi:10.1016/j.neubiorev.2011.04.011
[5]	Kable, J.W. and Glimcher, P.W. (2007) The neural correlates of subjective value during intertemporal choice. Nature Neuroscience, 10, 1625-1633. doi:10.1038/nn2007
[6]	McClure, S.M., Laibson, D.I., Loewenstein, G. and Cohen, J.D. (2004) Separate neural systems value immediate and delayed monetary rewards. Science, 306, 503-507. doi:10.1126/science.1100907
[7]	McClure, S.M., Ericson, K.M., Laibson, D.I., Loewenstein, G. and Cohen, J.D. (2007) Time discounting for primary rewards. Journal of Neuroscience, 27, 5796-5804. doi:10.1523/JNEUROSCI.4246-06.2007
[8]	Yu, R. (2012) Regional white matter volumes correlate with delay discounting. PLoS One, 7, e32595. doi:10.1371/journal.pone.0032595
[9]	Mazur, J.E. (1987) An adjusting procedure for studying delayed reinforcement. In: Commons, M. L., Mazur, J. E., Nevin, J. A. and Rachlin, H., Eds., The Effect of Delay and of Intervening Events on Reinforcement Value, Quantitative Analyses of Behavior, Erlbaum, Hillsdale, New Jersey, 55-73.
[10]	Bickel, W.K. and Marsch, L.A. (2001) Toward a behavioral economic understanding of drug dependence: Delay discounting processes. Addiction, 96, 73-86. doi:10.1046/j.1360-0443.2001.961736.x
[11]	Frederick, S., Loewenstein, G. and O’Donoghue, T. (2002) Time discounting and time preference: A critical review. Journal of Economic Literature, 40, 351-401. doi:10.1257/002205102320161311
[12]	Prelec, D. (2004) Decreasing impatience: A criterion for non-stationary time preference and “Hyperbolic” discounting. Scandinavian Journal of Economics, 106, 511-532. doi:10.1111/j.0347-0520.2004.00375.x
[13]	Ainslie, G. (2005) Precis of breakdown of will. Behavioral and Brain Sciences, 28, 635-650. doi:10.1017/S0140525X05000117
[14]	Takahashi, T. (2005) Loss of self-control in intertemporal choice may be attributable to logarithmic time-perception. Medical Hypotheses, 65, 691-693. doi:10.1016/j.mehy.2005.04.040
[15]	Bickel, W.K., Miller, M.L., Yi, R., Kowal, B.P., Lindquist, D.M. and Pitcock, J.A. (2006) Behavioral and neuroeconomics of drug addiction: Competing neural systems and temporal discounting processes. Drug and Alcohol Dependence, 90, S85-S91.
[16]	Reynolds, B. (2006) A review of delay-discounting research with humans: Relations to drug use and gambling. Behavioural Pharmacology, 17, 651-667. doi:10.1097/FBP.0b013e3280115f99
[17]	Petry, N.M. (2002) Discounting of delayed rewards in substance abusers: Relationship to antisocial personality disorder. Psychopharmacology, 162, 425-432. doi:10.1007/s00213-002-1115-1
[18]	Bickel, W.K., Odum, A.L. and Madden, G.J. (1999) Impulsivity and cigarette smoking: Delay discounting in current, never, and ex-smokers. Psychopharmacology, 146, 447-454. doi:10.1007/PL00005490
[19]	Kirby, K.N., Petry, N.M. and Bickel, W.K. (1999) Heroin addicts have higher discount rates for delayed rewards than non-drug-using controls. Journal of Experimental Psychology. General, 128, 78-87. doi:10.1037/0096-3445.128.1.78
[20]	Coffey, S.F., Gudleski, G.D., Saladin, M.E. and Brady, K.T. (2003) Impulsivity and rapid discounting of delayed hypothetical rewards in cocaine-dependent individuals. Experimental and Clinical Psychopharmacology, 11, 18-25. doi:10.1037/1064-1297.11.1.18
[21]	MacKillop, J., Anderson, E.J., Castelda, B.A., Mattson, R.E. and Donovick, P.J. (2006) Divergent validity of measures of cognitive distortions, impulsivity, and time perspective in pathological gambling. Journal of Gambling Studies, 22, 339-354. doi:10.1007/s10899-006-9021-9
[22]	Petry, N.M., Kirby, K.N. and Kranzler, H.R. (2002) Effects of gender and family history of alcohol dependence on a behavioral task of impulsivity in healthy subjects. Journal of Studies on Alcohol, 63, 83-90.
[23]	Sozou, P.D. (1998) On hyperbolic discounting and uncertain hazard rates. Proceedings of the Royal Society of London. Series B, 265, 2015-2020. doi:10.1098/rspb.1998.0534
[24]	Crean, J., Richards, J.B. and de Wit, H. (2002) Effect of tryptophan depletion on impulsive behavior in men with or without a family history of alcoholism. Behavioural Brain Research, 136, 349-357. doi:10.1016/S0166-4328(02)00132-8
[25]	Reynolds, B., Karraker, K., Horn, K. and Richards, J.B. (2003) Delay and probability discounting as related to different stages of adolescent smoking and non-smoking. Behavioural Processes, 64, 333-344. doi:10.1016/S0376-6357(03)00168-2
[26]	Reynolds, B. and Schiffbauer, R. (2004) Measuring state changes in human delay discounting: An experiential discounting task. Behavioural Processes, 67, 343-356.
[27]	Ohmura, Y., Takahashi, T. and Kitamura, N. (2005) Discounting delayed and probabilistic monetary gains and losses by smokers of cigarettes. Psychopharmacology, 182, 508-515. doi:10.1007/s00213-005-0110-8
[28]	Ohmura, Y., Takahashi, T., Kitamura, N. and Wehr, P. (2006) Three-month stability of delay and probability discounting measures. Experimental and Clinical Psychopharmacology, 14, 318-328. doi:10.1037/1064-1297.14.3.318
[29]	Estle, S.J., Green, L., Myerson, J. and Holt, D.D. (2007) Discounting of monetary and directly consumable rewards. Psychological Science, 18, 58-63. doi:10.1111/j.1467-9280.2007.01849.x
[30]	Takahashi, T., Oono, H. and Radford, M.H.B. (2007) Empirical estimation of consistency parameter in intertemporal choice based on Tsallis’ statistics. Physica A, 381, 338-342. doi:10.1016/j.physa.2007.03.038
[31]	Sellitto, M., Ciaramelli, E. and di Pellegrino, G. (2011) The neurobiology of intertemporal choice: Insight from imaging and lesion studies. Reviews in the Neurosciences, 22, 565-574. doi:10.1515/RNS.2011.046
[32]	Dayan, P. and Abbott, L.F. (2001) Theoretical Neuroscience. MIT Press, Cambridge.
[33]	Schultz, W. (2004) Neural coding of basic reward terms of animal learning theory, game theory, microeconomics and behavioural ecology. Current Opinion in Neurobiology, 14, 139-147. doi:10.1016/j.conb.2004.03.017
[34]	Takahashi, T., Ikeda, K. and Hasegawa, T. (2007) A hyperbolic decay of subjective probability of obtaining delayed rewards. Behavioral and Brain Functions, 25, 3-52.
[35]	Simon, N.W., Montgomery, K.S., Beas, B.S., Mitchell, M.R., LaSarge, C.L., Mendez, I.A., Banuelos, C., Vokes, C.M., Taylor, A.B., Haberman, R.P., Bizon, J.L. and Setlow, B. (2011) Dopaminergic modulation of risky decision-making. Journal of Neuroscience, 31, 17460-17470. doi:10.1523/JNEUROSCI.3772-11.2011
[36]	Heerey, E.A., Robinson, B.M., McMahon, R.P. and Gold, J.M. (2007) Delay discounting in schizophrenia. Cognitive Neuropsychiatry, 12, 213-221. doi:10.1080/13546800601005900
[37]	Colzato, L.S., van den Wildenberg, W.P., Van der Does, A.J. and Hommel, B. (2010) Genetic markers of striatal dopamine predict individual differences in dysfunctional, but not functional impulsivity. Neuroscience, 170, 782-788. doi:10.1016/j.neuroscience.2010.07.050
[38]	Eisenberg, D.T.A., MacKillop, J., Modi, M., Beauchemin, J., Dang, D., Lisman, S.A., Lum, J.K. and Wilson, D.S. (2007) Examining impulsivity as an endophenotype using a behavioral approach: A DRD2 TaqI A and DRD4 48-bp VNTR association study. Behavioral and Brain Functions, 3, 2. doi:10.1186/1744-9081-3-2
[39]	Young, R.M., Lawford, B.R., Nutting, A. and Noble, E.P. (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. Addictive Behaviours, 29, 1275-1294. doi:10.1016/j.addbeh.2004.06.012
[40]	Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R. and Dunbar, G.C. (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry, 59, 22-57.
[41]	American Psychiatric Association, (2000) Diagnostic and statistical manual of mental disorders, 4th Edition, text revision: DSM-IV-TR. American Psychiatric Press, Washington DC.
[42]	Hirsh, J.B., Morisano, D. and Peterson, J.B. (2008) Delay discounting: Interactions between personality and cognitive ability. Journal of Research in Personality, 42, 1646-1650. doi:10.1016/j.jrp.2008.07.005
[43]	Kirby, K.N. (2009). One-year temporal stability of delaydiscount rates. Psychonomic Bulletin & Review, 16, 457-462. doi:10.3758/PBR.16.3.457
[44]	Takahashi, T., Sakaguchi, K., Oki, M., Homma, S. and Hasegawa, T. (2006) Testosterone levels and discounting delayed monetary gains and losses in male humans. Neuro Endocrinology Letters, 27, 439-444.
[45]	Takahashi, T., Ikeda, K., Fukushima, H. and Hasegawa, T. (2007) Salivary-alpha amylase levels and hyperbolic discounting in male human. Neuro Endocrinology Letters, 28, 101-104.
[46]	Takahashi, T., Shinada, M., Inukai, K., Tanida, S., Takahashi, C., Mifune, N., Takagishi, H., Horita, Y., Hashimoto, H., Yokota, K., Kameda, T. and Yamagishi, T. (2010) Stress hormones predict hyperbolic time-discount rates six months later in adults. Neuro Endocrinology Letters, 31, 616-621.
[47]	Kawamura, Y., Takahashi, T., Liu, X., Nishida, N., Tokunaga, K., Ukawa, K., Noda, Y., Yoshikawa, A., Shimada, T., Umekage, T. and Sasaki, T. (In Press) DNA polymorphism in the FKBP5 gene affects impulsivity in intertemporal choice. Asia-Pacific Psychiatry. doi:10.1111/appy.12009
[48]	Promega Corp. (2005) Technical manual: Wizard genomic DNA purification kit: Instructions for use of products A1120, A1123, A1125 and A1620. Promega Corp., Madison.
[49]	Nishida, N., Tanabe, T., Hashido, K., Hirayasu, K., Takasu, M., Suyama, A. and Tokunaga, K. (2005) DigiTag assay for multiplex single nucleotide polymorphism typing with high success rate. Analytical Biochemistry, 346, 281-288. doi:10.1016/j.ab.2005.08.007
[50]	Nishida, N., Tanabe, T., Takasu, M., Suyama, A. and Tokunaga, K. (2007) Further development of multiplex single nucleotide polymorphism typing method, the DigiTag2 assay. Analytical Biochemistry, 364, 78-85. doi:10.1016/j.ab.2007.02.005
[51]	Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M.A., Bender, D., Maller, J., Sklar, P., de Bakker, P.I., Daly, M.J. and Sham, P.C. (2007) PLINK: A tool set for whole-genome association and populationbased linkage analyses. American Journal of Human Genetics, 81, 559-575. doi:10.1086/519795
[52]	Good, P. (2000) Permutation tests: A practical guide to resampling methods for testing hypothesis. Second Edition, Springer-Verlag, New York.
[53]	Hochberg, Y. and Tamhane, A.C. (1987) Multiple comparison procedures: Probability and mathematical statistics. Wiley-Interscience, New York. doi:10.1002/9780470316672
[54]	Cohen, J. (1988) Statistical power analysis for the behaviorral sciences. Second Edition, Lawrence Erlbaum, Hillsdale.
[55]	Field, A. (2005) Discovering statistics using SPSS. Second Edition, Sage Publications, London.
[56]	Gauderman, W.J. (2002) Sample size requirements for matched case-control studies of gene-environment interaction. Statistics in Medicine, 21, 35-50. doi:10.1002/sim.973
[57]	SPSS Inc. (2007) SPSS base 16.0 user’s guide. SPSS Inc., Chicago.
[58]	DeVona, J. (2005) Delay discounting task. Binghamton, New York.
[59]	Tachibana, Y. and Hikosaka O. (2012) The primate ventral pallidum encodes expected reward value and regulates motor action. Neuron, 76, 826-837. doi:10.1016/j.neuron.2012.09.030