Skip to main content Accessibility help

Modulation of orbitofrontal-striatal reward activity by dopaminergic functional polymorphisms contributes to a predisposition to alcohol misuse in early adolescence

  • Travis E. Baker (a1), Natalie Castellanos-Ryan (a1), Gunter Schumann (a2) (a3), Anna Cattrell (a2) (a3), Herta Flor (a4), Frauke Nees (a4), Tobias Banaschewski (a5), Arun Bokde (a6), Rob Whelan (a6), Christian Buechel (a7), Uli Bromberg (a7), Dimitri Papadopoulos Orfanos (a8), Juergen Gallinat (a9), Hugh Garavan (a10), Andreas Heinz (a9), Henrik Walter (a9), Rüdiger Brühl (a11), Penny Gowland (a12), Tomáš Paus (a13), Luise Poustka (a5), Jean-Luc Martinot (a13), Herve Lemaitre (a14), Eric Artiges (a1) (a3), Marie-Laure Paillère Martinot (a1) (a3), Michael N. Smolka (a15), Patricia Conrod (a1) (a2) and the IMAGEN consortium (a1) (a2) (a3) (a4) (a5) (a6) (a7) (a8) (a9) (a10) (a11) (a12) (a13) (a14) (a15)...



Abnormalities in reward circuit function are considered a core feature of addiction. Yet, it is still largely unknown whether these abnormalities stem from chronic drug use, a genetic predisposition, or both.


In the present study, we investigated this issue using a large sample of adolescent children by applying structural equation modeling to examine the effects of several dopaminergic polymorphisms of the D1 and D2 receptor type on the reward function of the ventral striatum (VS) and orbital frontal cortex (OFC), and whether this relationship predicted the propensity to engage in early alcohol misuse behaviors at 14 years of age and again at 16 years of age.


The results demonstrated a regional specificity with which the functional polymorphism rs686 of the D1 dopamine receptor (DRD1) gene and Taq1A of the ANKK1 gene influenced medial and lateral OFC activation during reward anticipation, respectively. Importantly, our path model revealed a significant indirect relationship between the rs686 of the DRD1 gene and early onset of alcohol misuse through a medial OFC × VS interaction.


These findings highlight the role of D1 and D2 in adjusting reward-related activations within the mesocorticolimbic circuitry, as well as in the susceptibility to early onset of alcohol misuse.


Corresponding author

Author for correspondence: Travis E. Baker, PhD, Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, USA. E-mail:


Hide All
Abi-Dargham, A (2004) Do we still believe in the dopamine hypothesis? New data bring new evidence. International Journal of Neuropsychopharmacology 7, S1S5.
Aiken, LS and West, SG (1991) Multiple Regression: Testing and Interpreting Interactions. Newbury Park, London: Sage.
Assadi, SM, Yucel, M and Pantelis, C (2009) Dopamine modulates neural networks involved in effort-based decision-making. Neuroscience Biology Behavior Review 33, 383393.
Baker, TE, Stockwell, T and Holroyd, CB (2013) Constraints on decision making: implications from genetics, personality, and addiction. Cognitive Affective Behavioral Neuroscience 13, 417436.
Balodis, IM and Potenza, MN (2015) Anticipatory reward processing in addicted populations: a focus on the monetary incentive delay task. Biological Psychiatry 77, 434444.
Batel, P, Houchi, H, Daoust, M, Ramoz, N, Naassila, M and Gorwood, P (2008) A haplotype of the DRD1 gene is associated with alcohol dependence. Alcohol: Clinical and Experimental Research 32, 567572.
Benjamini, Y and Hochberg, Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. Series B (Methodological) 57, 289300.
Blum, K, Braverman, ER, Holder, JM, Lubar, JF, Monastra, VJ, Miller, D, Lubar, JO, Chen, TJ and Comings, DE (2000) Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. Journal of Psychoactive Drugs 32(suppl.), i112.
Blum, K, Noble, EP, Sheridan, PJ, Montgomery, A, Ritchie, T, Ozkaragoz, T, Fitch, RJ, Wood, R, Finley, O and Sadlack, F (1993) Genetic predisposition in alcoholism: association of the D2 dopamine receptor TaqI B1 RFLP with severe alcoholics. Alcohol 10, 5967.
Bohn, MJ, Babor, TF and Kranzler, HR (1995) The Alcohol Use Disorders Identification Test (AUDIT): validation of a screening instrument for use in medical settings. Journal of the Study of Alcohol 56, 423432.
Casey, BJ (2015) Beyond simple models of self-control to circuit-based accounts of adolescent behavior. Annual Review of Psychology 66, 295319.
Casey, BJ, Jones, RM and Hare, TA (2008) The adolescent brain. Annals of the New York Academy of Sciences 1124, 111126.
Castellanos-Ryan, N, Struve, M, Whelan, R, Banaschewski, T, Barker, GJ, Bokde, AL, Bromberg, U, Büchel, C, Flor, H, Fauth-Bühler, M, Frouin, V, Gallinat, J, Gowland, P, Heinz, A, Lawrence, C, Martinot, JL, Nees, F, Paus, T, Pausova, Z, Rietschel, M, Robbins, TW, Smolka, MN, Schumann, G, Garavan, H, Conrod, PJ and IMAGEN Consortium (2014) Neural and cognitive correlates of the common and specific variance across externalizing problems in young adolescence. American Journal of Psychiatry 171, 13101319.
Cetin, T, Freudenberg, F, Fuchtemeier, M and Koch, M (2004) Dopamine in the orbitofrontal cortex regulates operant responding under a progressive ratio of reinforcement in rats. Neuroscience Letters 370, 114117.
Cohen, MX, Young, J, Baek, JM, Kessler, C and Ranganath, C (2005) Individual differences in extraversion and dopamine genetics predict neural reward responses. Cognitive Brain Research 25, 851861.
Comings, DE and Blum, K (2000) Reward deficiency syndrome: genetic aspects of behavioral disorders. Progress in Brain Research 126, 325341.
Comings, DE, Gade, R, Wu, S, Chiu, C, Dietz, G, Muhleman, D, Saucier, G, Ferry, L, Rosenthal, RJ, Lesieur, HR, Rugle, LJ and MacMurray, P (1997) Studies of the potential role of the dopamine D1 receptor gene in addictive behaviors. Molecular Psychiatry 2, 4456.
Conrod, PJ and Nikolaou, K (2016) Annual research review: on the developmental neuropsychology of substance use disorders. Journal of Child Psychology and Psychiatry 57, 371394.
Cools, R and D'Esposito, M (2011) Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biological Psychiatry 69, e113e125.
Cox, SM, Frank, MJ, Larcher, K, Fellows, LK, Clark, CA, Leyton, M and Dagher, A (2015) Striatal D1 and D2 signaling differentially predict learning from positive and negative outcomes. Neuroimage 109, 95101.
Dawson, JF (2014) Moderation in management research: what, why, when and how. Journal of Business and Psychology 29, 119.
Dawson, JF and Richter, AW (2006) Probing three-way interactions in moderated multiple regression: development and application of a slope difference test. Journal of Applied Psychology 91, 917926.
Diekhof, EK, Kaps, L, Falkai, P and Gruber, O (2012) The role of the human ventral striatum and the medial orbitofrontal cortex in the representation of reward magnitude – an activation likelihood estimation meta-analysis of neuroimaging studies of passive reward expectancy and outcome processing. Neuropsychologia 50, 12521266.
Durstewitz, D and Seamans, JK (2002) The computational role of dopamine D1 receptors in working memory. Neural Networks 15, 561572.
Elliott, R, Agnew, Z and Deakin, JF (2008) Medial orbitofrontal cortex codes relative rather than absolute value of financial rewards in humans. European Journal of Neuroscience 27, 22132218.
Elliott, R and Deakin, B (2005) Role of the orbitofrontal cortex in reinforcement processing and inhibitory control: evidence from functional magnetic resonance imaging studies in healthy human subjects. International Review of Neurobiology 65, 89116.
Elliott, R, Dolan, RJ and Frith, CD (2000) Dissociable functions in the medial and lateral orbitofrontal cortex: evidence from human neuroimaging studies. Cerebral Cortex 10, 308317.
Frank, MJ and Claus, ED (2006) Anatomy of a decision: striato-orbitofrontal interactions in reinforcement learning, decision making, and reversal. Psychological Review 113, 300326.
Frank, MJ and Hutchison, K (2009) Genetic contributions to avoidance-based decisions: striatal D2 receptor polymorphisms. Neuroscience 164, 131140.
Frank, MJ, Moustafa, AA, Haughey, HM, Curran, T and Hutchison, KE (2007) Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning. Proceedings of the National Academy of Sciences of the United States of America 104, 1631116316.
Frankenstein, U, Wennerberg, A, Richter, W, Bernstein, C, Morden, D, Florence, R and Mcintyre, M (2002) Activation and Deactivation in BOLD fMRI. Concepts in Magnetic Resonance 16, 6370.
Galvan, A, Hare, TA, Parra, CE, Penn, J, Voss, H, Glover, G and Casey, BJ (2006) Earlier development of the accumbens relative to orbitofrontal cortex might underlie risk-taking behavior in adolescents. Journal of Neuroscience 26, 68856892.
Garske, AK, Lawyer, CR, Peterson, BM and Illig, KR (2013) Adolescent changes in dopamine D1 receptor expression in orbitofrontal cortex and piriform cortex accompany an associative learning deficit. PLoS ONE 8, e56191.
Hikosaka, K and Watanabe, M (2000) Delay activity of orbital and lateral prefrontal neurons of the monkey varying with different rewards. Cerebral Cortex 10, 263271.
Hu, L and Bentler, P (1999) Cutoff criteria for fit indices in covariance structure analysis: conventional criteria versus new alternatives. Structural Equation Modeling 6, 155.
Huang, W and Li, MD (2009) Differential allelic expression of dopamine D1 receptor gene (DRD1) is modulated by microRNA miR-504. Biological Psychiatry 65, 702705.
Huang, W, Ma, JZ, Payne, TJ, Beuten, J, Dupont, RT and Li, MD (2008) Significant association of DRD1 with nicotine dependence. Human Genetics 123, 133140.
Hurd, YL, Suzuki, M and Sedvall, GC (2001) D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain. Journal of Chemical Neuroanatomy 22, 127137.
Ikemoto, S, Glazier, BS, Murphy, JM and McBride, WJ (1997) Role of dopamine D1 and D2 receptors in the nucleus accumbens in mediating reward. Journal of Neuroscience 17, 85808587.
Klein, TA, Neumann, J, Reuter, M, Hennig, J, von Cramon, DY and Ullsperger, M (2007) Genetically determined differences in learning from errors. Science 318, 16421645.
Knutson, B and Heinz, A (2015) Probing psychiatric symptoms with the monetary incentive delay task. Biological Psychiatry 77, 418420.
Knutson, B, Westdorp, A, Kaiser, E and Hommer, D (2000) FMRI visualization of brain activity during a monetary incentive delay task. Neuroimage 12, 2027.
Laruelle, M, Gelernter, J and Innis, RB (1998) D2 receptors binding potential is not affected by Taq1 polymorphism at the D2 receptor gene. Molecular Psychiatry 3, 261265.
Lutz, K and Widmer, M (2014) What can the monetary incentive delay task tell us about the neural processing of reward and punishment. Neuroscience and Neuroeconomics 3, 3345.
Maldjian, JA, Laurienti, PJ, Kraft, RA and Burdette, JH (2003) An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fmri data sets. NeuroImage 19, 12331239.
McClure, SM and Bickel, WK (2014) A dual-systems perspective on addiction: contributions from neuroimaging and cognitive training. Annals of the New York Academy of Sciences 1327, 6278.
Meyer-Lindenberg, A, Straub, RE, Lipska, BK, Verchinski, BA, Goldberg, T, Callicott, JH, Egan, MF, Huffaker, SS, Mattay, VS, Kolachana, B, Kleinman, JE and Weinberger, DR (2007) Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. Journal of Clinical Investigations 117, 672682.
Munafo, MR, Matheson, IJ and Flint, J (2007) Association of the DRD2 gene Taq1A polymorphism and alcoholism: a meta-analysis of case-control studies and evidence of publication bias. Molecular Psychiatry 12, 454461.
Nees, F, Tzschoppe, J, Patrick, CJ, Vollstädt-Klein, S, Steiner, S, Poustka, L, Banaschewski, T, Barker, GJ, Büchel, C, Conrod, PJ, Garavan, H, Heinz, A, Gallinat, J, Lathrop, M, Mann, K, Artiges, E, Paus, T, Poline, JB, Robbins, TW, Rietschel, M, Smolka, MN, Spanagel, R, Struve, M, Loth, E, Schumann, G, Flor, H, IMAGEN Consortium (2012) Determinants of early alcohol use in healthy adolescents: the differential contribution of neuroimaging and psychological factors. Neuropsychopharmacology 37:986995.
Noble, EP (1994) Polymorphisms of the D2 dopamine receptor gene and alcoholism and other substance use disorders. Alcohol 2, 3543.
Noble, EP (1998) The D2 dopamine receptor gene: a review of association studies in alcoholism and phenotypes. Alcohol 16, 3345.
Noble, EP (2000) The DRD2 gene in psychiatric and neurological disorders and its phenotypes. Pharmacogenomics 1, 309333.
Noble, EP (2003) D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. American Journal of Medical Genetics 116, 103125.
Noble, EP, Syndulko, K, Fitch, RJ, Ritchie, T, Bohlman, MC, Guth, P, Sheridan, PJ, Montgomery, A, Heinzmann, C and Sparkes, RS (1994) D2 dopamine receptor TaqI A alleles in medically ill alcoholic and nonalcoholic patients. Alcohol 29, 729744.
Nymberg, C, Banaschewski, T, Bokde, AL, Buchel, C, Conrod, P, Flor, H, Frouin, V, Garavan, H, Gowland, P, Heinz, A, Ittermann, B, Mann, K, Martinot, JL, Nees, F, Paus, T, Pausova, Z, Rietschel, , Robbins, TW, Smolka, MN, Ströhle, A, Schumann, G, Klingberg, T and IMAGEN consortium (2014) DRD2/ANKK1 polymorphism modulates the effect of ventral striatal activation on working memory performance. Neuropsychopharmacology 39. 23572365.
O'Doherty, J, Kringelbach, ML, Rolls, ET, Hornak, J and Andrews, C (2001) Abstract reward and punishment representations in the human orbitofrontal cortex. Nature Neuroscience 4, 95102.
Pujara, M and Koenigs, M (2014) Mechanisms of reward circuit dysfunction in psychiatric illness: prefrontal-striatal interactions. Neuroscientist 20, 8295.
Redish, AD, Jensen, S and Johnson, A (2008) A unified framework for addiction: vulnerabilities in the decision process. Behavior Brain Science 31, 415437.
Schneider, S, Peters, J, Bromberg, U, Brassen, S, Miedl, SF, Banaschewski, T, Barker, GJ, Conrod, P, Flor, H, Garavan, H, Heinz, A, Ittermann, B, Lathrop, M, Loth, E, Mann, K, Martinot, JL, Nees, F, Paus, T, Rietschel, M, Robbins, TW, Smolka, MN, Spanagel, R, Ströhle, A, Struve, M, Schumann, G, Büchel, C and IMAGEN Consortium (2012) Risk taking and the adolescent reward system: a potential common link to substance abuse. American Journal of Psychiatry 169, 3946.
Schoenbaum, G and Shaham, Y (2008) The role of orbitofrontal cortex in drug addiction: a review of preclinical studies. Biological Psychiatry 63, 256262.
Schultz, W (2001) Reward signaling by dopamine neurons. Neuroscientist 7, 293302.
Schultz, W (2010) Dopamine signals for reward value and risk: basic and recent data. Behavior and Brain Function 6, 24.
Schultz, W, Tremblay, L and Hollerman, JR (2000) Reward processing in primate orbitofrontal cortex and basal ganglia. Cerebral Cortex 10, 272284.
Schumann, G, Loth, E, Banaschewski, T, Barbot, A, Barker, G, Buchel, C, Conrod, PJ, Dalley, JW, Flor, H, Gallinat, J, Garavan, H, Heinz, A, Itterman, B, Lathrop, M, Mallik, C, Mann, K, Martinot, JL, Paus, T, Poline, JB, Robbins, TW, Rietschel, M, Reed, L, Smolka, M, Spanagel, R, Speiser, C, Stephens, DN, Ströhle, A, Struve, M and IMAGEN consortium (2010) The IMAGEN study: reinforcement-related behaviour in normal brain function and psychopathology. Molecular Psychiatry 15, 11281139.
Suhara, T and Miyoshi, M (2007) Distribution and function of dopamine D1, D2 receptor. Rinsho Shinkeigaku 47, 826828.
Svenningsson, P, Nishi, A, Fisone, G, Girault, JA, Nairn, AC and Greengard, P (2004) DARPP-32: an integrator of neurotransmission. Annual Review of Pharmacology and Toxicology 44, 269296.
Thompson, J, Thomas, N, Singleton, A, Piggott, M, Lloyd, S, Perry, EK, Morris, CM, Perry, RH, Ferrier, IN and Court, JA (1997) D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics 7, 479484.
Volkow, ND, Fowler, JS, Wang, GJ, Baler, R and Telang, F (2009) Imaging dopamine's role in drug abuse and addiction. Neuropharmacology 56, 38.
Volkow, ND, Wang, GJ, Fowler, JS and Tomasi, D (2012) Addiction circuitry in the human brain. Annual Review of Pharmacology and Toxicology 52, 321336.
Volkow, ND, Wang, GJ, Fowler, JS, Tomasi, D and Telang, F (2011) Addiction: beyond dopamine reward circuitry. Proceedings of the National Academy of Sciences of the United States of America USA 108, 1503715042.
Whelan, R, Conrod, PJ, Poline, JB, Lourdusamy, A, Banaschewski, T, Barker, GJ, Bellgrove, MA, Büchel, C, Byrne, M, Cummins, TD, Fauth-Bühler, M, Flor, H, Gallinat, J, Heinz, A, Ittermann, B, Mann, K, Martinot, JL, Lalor, EC, Lathrop, M, Loth, E, Nees, F, Paus, T, Rietschel, M, Smolka, MN, Spanagel, R, Stephens, DN, Struve, M, Thyreau, B, Vollstaedt-Klein, S, Robbins, TW, Schumann, G, Garavan, H and IMAGEN Consortium (2012) Adolescent impulsivity phenotypes characterized by distinct brain networks. Nature Neuroscience 15, 920925.
Zhang, Y, Bertolino, A, Fazio, L, Blasi, G, Rampino, A, Romano, R, Lee, ML, Xiao, T, Papp, A, Wang, D and Sadée, W (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, 2055220557.
Zhu, F, Yan, CX, Wen, YC, Wang, J, Bi, J, Zhao, YL, Wei, L, Gao, CG, Jia, W and Li, SB (2013) Dopamine D1 receptor gene variation modulates opioid dependence risk by affecting transition to addiction. PLoS ONE 8, e70805.


Type Description Title
Supplementary materials

Baker et al. supplementary material 1
Supplementary Table

 Unknown (90 KB)
90 KB


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed