Abstract
Dopamine D2 receptors mediate the rewarding effects of many drugs of abuse. In humans, several polymorphisms in DRD2, the gene encoding these receptors, increase our genetic risk for developing addictive disorders. Here, we examined one of the most frequently studied candidate variant for addiction in DRD2 for association with brain structure. We tested whether this variant showed associations with regional brain volumes across two independent elderly cohorts, totaling 1,032 subjects. We first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI1). We hypothesized that this addiction-related polymorphism would be associated with structural brain differences in regions previously implicated in familial vulnerability for drug dependence. Then, we assessed the generalizability of our findings by testing this polymorphism in a non-overlapping replication sample of 294 elderly subjects from a continuation of the first ADNI project (ADNI2) to minimize the risk of reporting false positive results. In both cohorts, the minor allele—previously linked with increased risk for addiction—was associated with larger volumes in various brain regions implicated in reward processing. These findings suggest that neuroanatomical phenotypes associated with familial vulnerability for drug dependence may be partially mediated by DRD2 genotype.
References
Aisen, P. S., Petersen, R. C., Donohue, M. C., Gamst, A., Raman, R., Thomas, R. G., et al. (2010). Clinical core of the Alzheimer’s Disease Neuroimaging Initiative: progress and plans. Alzheimer’sDement, 6, 239–246.
Alexander, G. E., DeLong, M. R., & Strick, P. L. (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience, 9, 357–381.
Benes, F. M., Paskevich, P. A., Davidson, J., & Domesick, V. B. (1985). The effects of haloperidol on synaptic patterns in the rat striatum. Brain Research, 329, 265–273.
Bertolino, A., Fazio, L., Caforio, G., Blasi, G., Rampino, A., Romano, R., et al. (2009). Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia. Brain, 132, 417–425.
Bertolino, A., Taurisano, P., Pisciotta, N. M., Blasi, G., Fazio, L., Romano, R., et al. (2010). Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance. PLoS One, 5, e9348.
Blasi, G., Lo Bianco, L., Taurisano, P., Gelao, B., Romano, R., Fazio, L., 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. Journal of Neuroscience, 29, 14812–14819.
Chakos, M. H., Shirakawa, O., Lieberman, J., Lee, H., Bilder, R., & Tamminga, C. A. (1998). Striatal enlargement in rats chronically treated with neuroleptic. Biological Psychiatry, 44, 675–684.
Chung, M. K., Worsley, K. J., Paus, T., Cherif, C., Collins, D. L., Giedd, J. N., et al. (2001). A unified statistical approach to deformation-based morphometry. NeuroImage, 14, 595–606.
Collins, D. L., Neelin, P., Peters, T. M., & Evans, A. C. (1994). Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. Journal of Computer Assisted Tomography, 18, 192–205.
Corson, P. W., Nopoulos, P., Miller, D. D., Arndt, S., & Andreasen, N. C. (1999). Change in basal ganglia volume over 2 years in patients with schizophrenia: typical versus atypical neuroleptics. The American Journal of Psychiatry, 156, 1200–1204.
Dalley, J. W., Fryer, T. D., Brichard, L., Robinson, E. S., Theobald, D. E., Laane, K., et al. (2007). Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science, 315, 1267–1270.
David, S. P., Strong, D. R., Munafo, M. R., Brown, R. A., Lloyd-Richardson, E. E., Wileyto, P. E., et al. (2007). Bupropion efficacy for smoking cessation is influenced by the DRD2 Taq1A polymorphism: analysis of pooled data from two clinical trials. Nicotine & Tobacco Research, 9, 1251–1257.
Doehring, A., Hentig, N., Graff, J., Salamat, S., Schmidt, M., Geisslinger, G., et al. (2009). Genetic variants altering dopamine D2 receptor expression or function modulate the risk of opiate addiction and the dosage requirements of methadone substitution. Pharmacogenetics and Genomics, 19, 407–414.
ENIGMA2 (2012). ENIGMA2 Genetics support team, ENIGMA2 1KGP cookbook (v3) [Online] (Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium.).
Ersche, K. D., Jones, P. S., Williams, G. B., Smith, D. G., Bullmore, E. T., & Robbins, T. W. (2012a). Distinctive personality traits and neural correlates associated with stimulant drug use versus familial risk of stimulant dependence. Biological Psychiatry, 74, 137–144.
Ersche, K. D., Jones, P. S., Williams, G. B., Turton, A. J., Robbins, T. W., & Bullmore, E. T. (2012b). Abnormal brain structure implicated in stimulant drug addiction. Science, 335, 601–604.
Ersche, K. D., Williams, G. B., Robbins, T. W., & Bullmore, E. T. (2013). Meta-analysis of structural brain abnormalities associated with stimulant drug dependence and neuroimaging of addiction vulnerability and resilience. Current Opinion in Neurobiology, 23, 615–624.
Fazio, L., Blasi, G., Taurisano, P., Papazacharias, A., Romano, R., Gelao, B., et al. (2011). D2 receptor genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans. NeuroImage, 54, 2915–2921.
Frank, M. J., & Hutchison, K. (2009). Genetic contributions to avoidance-based decisions: striatal D2 receptor polymorphisms. Neuroscience, 164, 131–140.
Freeborough, P. A., & Fox, N. C. (1998). Modeling brain deformations in Alzheimer disease by fluid registration of serial 3D MR images. Journal of Computer Assisted Tomography, 22, 838–843.
Hibar, D. P., Stein, J. L., Ryles, A. B., Kohannim, O., Jahanshad, N., Medland, S. E., et al. (2013). Genome-wide association identifies genetic variants associated with lentiform nucleus volume in N = 1345 young and elderly subjects. Brain Imaging and Behavior, 7, 102–115.
Hua, X., Leow, A. D., Lee, S., Klunder, A. D., Toga, A. W., Lepore, N., et al. (2008a). 3D characterization of brain atrophy in Alzheimer’s disease and mild cognitive impairment using tensor-based morphometry. NeuroImage, 41, 19–34.
Hua, X., Leow, A. D., Parikshak, N., Lee, S., Chiang, M. C., Toga, A. W., et al. (2008b). Tensor-based morphometry as a neuroimaging biomarker for Alzheimer’s disease: an MRI study of 676 AD, MCI, and normal subjects. NeuroImage, 43, 458–469.
Hwang, R., Shinkai, T., De Luca, V., Muller, D. J., Ni, X., Macciardi, F., et al. (2005). Association study of 12 polymorphisms spanning the dopamine D(2) receptor gene and clozapine treatment response in two treatment refractory/intolerant populations. Psychopharmacology, 181, 179–187.
Isomura, Y., Takekawa, T., Harukuni, R., Handa, T., Aizawa, H., Takada, M., et al. (2013). Reward-modulated motor information in identified striatum neurons. Journal of Neuroscience, 33, 10209–10220.
Jack, C. R., Jr., Bernstein, M. A., Fox, N. C., Thompson, P., Alexander, G., Harvey, D., et al. (2008). The Alzheimer’s Disease Neuroimaging Initiative (ADNI): MRI methods. Journal of Magnetic Resonance Imaging, 27, 685–691.
Jovicich, J., Czanner, S., Greve, D., Haley, E., van der Kouwe, A., Gollub, R., et al. (2006). Reliability in multi-site structural MRI studies: effects of gradient non-linearity correction on phantom and human data. NeuroImage, 30, 436–443.
Keshavan, M. S., Bagwell, W. W., Haas, G. L., Sweeney, J. A., Schooler, N. R., & Pettegrew, J. W. (1994). Changes in caudate volume with neuroleptic treatment. Lancet, 344, 1434.
Koehler, S., Wacker, J., Odorfer, T., Reif, A., Gallinat, J., Fallgatter, A. J., et al. (2011). Resting posterior minus frontal EEG slow oscillations is associated with extraversion and DRD2 genotype. Biological Psychology, 87, 407–413.
Krebs, R. M., Boehler, C. N., Roberts, K. C., Song, A. W., & Woldorff, M. G. (2012). The involvement of the dopaminergic midbrain and cortico-striatal-thalamic circuits in the integration of reward prospect and attentional task demands. Cerebral Cortex, 22, 607–615.
Kunzle, H. (1975). Bilateral projections from precentral motor cortex to the putamen and other parts of the basal ganglia. An autoradiographic study in Macaca fascicularis. Brain Research, 88, 195–209.
Lander, E. S., & Schork, N. J. (1994). Genetic dissection of complex traits. Science, 265, 2037–2048.
Langers, D. R., Jansen, J. F., & Backes, W. H. (2007). Enhanced signal detection in neuroimaging by means of regional control of the global false discovery rate. NeuroImage, 38, 43–56.
Lawford, B., Barnes, M., Swagell, C., Connor, J., Burton, S., Heslop, K., Voisey, J., Morris, C., Nyst, P., Noble, E., et al. (2013). DRD2/ANKK1 Taq1A (rs 1800497C>T) genotypes are associated with susceptibility to second generation antipsychotic-induced akathisia. Journal of Psychopharmacology, 27, 343–348.
Lawford, B. R., Young, R. M., Rowell, J. A., Qualichefski, J., Fletcher, B. H., Syndulko, K., et al. (1995). Bromocriptine in the treatment of alcoholics with the D2 dopamine receptor A1 allele. Nature Medicine, 1, 337–341.
Le Foll, B., Gallo, A., Le Strat, Y., Lu, L., & Gorwood, P. (2009). Genetics of dopamine receptors and drug addiction: a comprehensive review. Behavioral Pharmacology, 20, 1–17.
Leow, A., Huang, S. C., Geng, A., Becker, J., Davis, S., Toga, A., et al. (2005). Inverse consistent mapping in 3D deformable image registration: its construction and statistical properties. Information Processing in Medical Imaging, 19, 493–503.
Leow, A. D., Klunder, A. D., Jack, C. R., Jr., Toga, A. W., Dale, A. M., Bernstein, M. A., et al. (2006). Longitudinal stability of MRI for mapping brain change using tensor-based morphometry. NeuroImage, 31, 627–640.
Lucht, M., Samochowiec, A., Samochowiec, J., Jasiewicz, A., Grabe, H. J., Geissler, I., et al. (2010). Influence of DRD2 and ANKK1 genotypes on apomorphine-induced growth hormone (GH) response in alcohol-dependent patients. Progress in Neuropsychopharmacology and Biological Psychiatry, 34, 45–49.
Mazziotta, J., Toga, A., Evans, A., Fox, P., Lancaster, J., Zilles, K., et al. (2001). A probabilistic atlas and reference system for the human brain: International Consortium for Brain Mapping (ICBM). Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 356, 1293–1322.
Morgan, D., Grant, K. A., Gage, H. D., Mach, R. H., Kaplan, J. R., Prioleau, O., et al. (2002). Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Nature Neuroscience, 5, 169–174.
Morton, L. M., Wang, S. S., Bergen, A. W., Chatterjee, N., Kvale, P., Welch, R., et al. (2006). DRD2 genetic variation in relation to smoking and obesity in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Pharmacogenetics and Genomics, 16, 901–910.
Mrazek, D. A. (2010). Psychiatric pharmacogenomics. New York: Oxford University Press.
Nader, M. A., Morgan, D., Gage, H. D., Nader, S. H., Calhoun, T. L., Buchheimer, N., et al. (2006). PET imaging of dopamine D2 receptors during chronic cocaine self-administration in monkeys. Nature Neuroscience, 9, 1050–1056.
Nieoullon, A. (2002). Dopamine and the regulation of cognition and attention. Progress in Neurobiology, 67, 53–83.
Noble, E. P., Zhang, X., Ritchie, T. L., & Sparkes, R. S. (2000). Haplotypes at the DRD2 locus and severe alcoholism. American Journal of Medical Genetics, 96, 622–631.
Riddle, W. R., Li, R., Fitzpatrick, J. M., DonLevy, S. C., Dawant, B. M., & Price, R. R. (2004). Characterizing changes in MR images with color-coded Jacobians. Magnetic Resonance Imaging, 22, 769–777.
Roussotte, F.F., Jahanshad, N., Hibar, D.P., Sowell, E.R., Kohannim, O., Barysheva, M., et al. (2013). A commonly carried genetic variant in the delta opioid receptor gene, OPRD1, is associated with smaller regional brain volumes: Replication in elderly and young populations. Human Brain Mapping. doi:10.1002/hbm.22247.
Sambataro, F., Fazio, L., Taurisano, P., Gelao, B., Porcelli, A., Mancini, M., et al. (2013). DRD2 Genotype-based variation of default mode network activity and of its relationship with striatal DAT binding. Schizophrenia Bulletin, 39, 206–216.
Sasabe, T., Furukawa, A., Matsusita, S., Higuchi, S., & Ishiura, S. (2007). Association analysis of the dopamine receptor D2 (DRD2) SNP rs1076560 in alcoholic patients. Neuroscience Letters, 412, 139–142.
Sasabe, T., & Ishiura, S. (2010). Alcoholism and alternative splicing of candidate genes. International Journal of Environmental Research and Public Health, 7, 1448–1466.
Scherk, H., & Falkai, P. (2006). Effects of antipsychotics on brain structure. Current Opinion in Psychiatry, 19, 145–150.
Schulz, K. F., & Grimes, D. A. (2002). Sample size slippages in randomised trials: exclusions and the lost and wayward. Lancet, 359, 781–785.
Sled, J. G., Zijdenbos, A. P., & Evans, A. C. (1998). A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Transactions on Medical Imaging, 17, 87–97.
Stein, J. L., Hibar, D. P., Madsen, S. K., Khamis, M., McMahon, K. L., de Zubicaray, G. I., et al. (2011). Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N = 1198) using genome-wide search. Molecular Psychiatry, 16(927–937), 881.
Stein, J. L., Hua, X., Morra, J. H., Lee, S., Hibar, D. P., Ho, A. J., et al. (2010). Genome-wide analysis reveals novel genes influencing temporal lobe structure with relevance to neurodegeneration in Alzheimer’s disease. NeuroImage, 51, 542–554.
Stein, J. L., Medland, S. E., Vasquez, A. A., Hibar, D. P., Senstad, R. E., Winkler, A. M., et al. (2012). Identification of common variants associated with human hippocampal and intracranial volumes. Nature Genetics, 44, 552–561.
Thompson, P. M., Bartzokis, G., Hayashi, K. M., Klunder, A. D., Lu, P. H., Edwards, N., et al. (2009). Time-lapse mapping of cortical changes in schizophrenia with different treatments. Cerebral Cortex, 19, 1107–1123.
Thompson, P. M., Giedd, J. N., Woods, R. P., MacDonald, D., Evans, A. C., & Toga, A. W. (2000). Growth patterns in the developing brain detected by using continuum mechanical tensor maps. Nature, 404, 190–193.
Volkow, N. D., Chang, L., Wang, G. J., Fowler, J. S., Ding, Y. S., Sedler, M., et al. (2001). Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. The American Journal of Psychiatry, 158, 2015–2021.
Volkow, N. D., Fowler, J. S., Wang, G. J., Hitzemann, R., Logan, J., Schlyer, D. J., et al. (1993). Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse, 14, 169–177.
Volkow, N. D., Fowler, J. S., Wang, G. J., & Swanson, J. M. (2004). Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Molecular Psychiatry, 9, 557–569.
Volkow, N. D., Wang, G. J., Fowler, J. S., Tomasi, D., Telang, F., & Baler, R. (2010). Addiction: decreased reward sensitivity and increased expectation sensitivity conspire to overwhelm the brain’s control circuit. Bioessays, 32, 748–755.
Volkow, N. D., Wang, G. J., Telang, F., Fowler, J. S., Logan, J., Jayne, M., et al. (2007). Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. Journal of Neuroscience, 27, 12700–12706.
Wise, R. A. (2004). Dopamine, learning and motivation. Nature Review Neuroscience, 5, 483–494.
Wolosin, S. M., Zeithamova, D., & Preston, A. R. (2013). Distributed hippocampal patterns that discriminate reward context are associated with enhanced associative binding. Journal of Experimental Psychology: General, 42, 1264–1276.
Zhang, Y., Bertolino, A., Fazio, L., Blasi, G., Rampino, A., Romano, R., et al. (2007). Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proceedings of the National Academy of Sciences of the United States of America, 104, 20552–20557.
Acknowledgments
F.F.R. was supported, in part, by a postdoctoral fellowship from the A. P. Giannini Foundation. This work was additionally supported by National Institute of Health grants (R01 MH097268, R01 AG040060) to P.M.T. Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Institute for Neuroimaging & Informatics at the University of Southern California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514.
Conflict of interest
Paul M. Thompson, Florence F. Roussotte, Neda Jahanshad, and Derrek P. Hibar declare that they have no conflicts of interest.
Informed consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, and the applicable revisions at the time of the investigation. Informed consent was obtained from all patients for being included in the study.
Author information
Authors and Affiliations
Consortia
Corresponding author
Additional information
Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf
Rights and permissions
About this article
Cite this article
Roussotte, F.F., Jahanshad, N., Hibar, D.P. et al. Altered regional brain volumes in elderly carriers of a risk variant for drug abuse in the dopamine D2 receptor gene (DRD2) . Brain Imaging and Behavior 9, 213–222 (2015). https://doi.org/10.1007/s11682-014-9298-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11682-014-9298-8