DRD2 Genotype-Based Variants Modulates D2 Receptor Distribution in Ventral Striatum

  • Mikaeel Valli
  • Sang Soo Cho
  • Mario Masellis
  • Robert Chen
  • Pablo Rusjan
  • Jinhee Kim
  • Yuko Koshimori
  • Alexander Mihaescu
  • Antonio P. StrafellaEmail author


Dopaminergic signaling within the striatum is crucial for motor planning and mental function. Neurons within the striatum contain two dopamine D2 receptor isoforms—D2 long and D2 short. The amount of expression for these receptor isoforms is affected by the genotype within two single nucleotide polymorphisms (SNPs), rs2283265 and rs1076560 (both are in high linkage disequilibrium; C > A), found in the DRD2 gene. However, it is unclear how these SNPs affect the distribution of D2 receptors in vivo within the nigrostriatal dopaminergic system. We aim to elucidate this with PET imaging in healthy young adults using [11C]-(+)-PHNO. Participants were genotyped for the DRD2 rs2283265 SNP and a total of 20 enrolled: 9 with CC, 6 with CA, and 5 with AA genotype. The main effect of genotype on [11C]-(+)-PHNO binding was tested and we found significant group effect within the ventral striatum. Specifically, CC and CA carriers had higher binding in this region compared to AA carriers. There were no observed differences between genotypes in other regions within the basal ganglia. Our preliminary results implicate that the polymorphism genotype affects the dopaminergic signaling by controlling either the quantity of D2 receptors, D2 affinity, or a combination thereof within the ventral striatum.


Dopamine D2 receptor DRD2 gene Positron emission tomography Single nucleotide polymorphism [11C]-(+)-PHNO radiotracer 



The authors thank the Psychiatric Neurogenetics Laboratory team for performing the genotyping; and Laura Nguyen, Anusha Ravichandran, Colin Cole, and Alvina Ng for their technical assistance.

Authors’ Contributions

Study conception and design: MV and APS

Data acquisition: MV and YK

Data analysis: MV, SSC, and PR

Data interpretation: MV and APS

Manuscript drafting: MV

Manuscript review and critique for important intellectual content: MV, SSC, MM, RC, PR, JK, YK, AM, and APS

Approved version to be published: MV and APS

Funding information

Dr. Antonio Strafella was supported by the Canadian Institutes of Health Research (CIHR) (MOP 136778) and the Canada Research Chair program. Mikaeel Valli was supported by the CIHR’s Canada Graduate Scholarship, Master’s Program. Dr. Robert Chen was supported by the Catherine Manson Chair in Movement Disorders.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in this study were in accordance with the standards of the Center for Addiction and Mental Health research ethics board (protocol reference number 106/2016) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.


  1. 1.
    Beaulieu J-M, Gainetdinov RR (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 63:182–217CrossRefGoogle Scholar
  2. 2.
    Missale C, Nash SR, Robinson SW et al (1998) Dopamine receptors: from structure to function. Physiol Rev 78:189–225. CrossRefPubMedGoogle Scholar
  3. 3.
    Ford C (2014) The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience 282:13–22. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Durieux PF, Schiffmann SN, de Kerchove d’Exaerde A (2012) Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions. EMBO J 31:640–653. CrossRefPubMedGoogle Scholar
  5. 5.
    Bello EP, Mateo Y, Gelman DM, Noaín D, Shin JH, Low MJ, Alvarez VA, Lovinger DM et al (2011) Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors. Nat Neurosci 14:1033–1038. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Nyberg L, Karalija N, Salami A, Andersson M, Wåhlin A, Kaboovand N, Köhncke Y, Axelsson J et al (2016) Dopamine D2 receptor availability is linked to hippocampal-caudate functional connectivity and episodic memory. Proc Natl Acad Sci U S A 113:7918–7923. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Cox SML, Frank MJ, Larcher K, Fellows LK, Clark CA, Leyton M, Dagher A (2015) Striatal D1 and D2 signaling differentially predict learning from positive and negative outcomes. Neuroimage 109:95–101. CrossRefPubMedGoogle Scholar
  8. 8.
    Buckholtz JW, Treadway MT, Cowan RL, Woodward ND, Li R, Ansari MS, Baldwin RM, Schwartzman AN et al (2010) Dopaminergic network differences in human impulsivity. Science 329:532. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Zald DH, Cowan RL, Riccardi P, Baldwin RM, Ansari MS, Li R, Shelby ES, Smith CE et al (2008) Midbrain dopamine receptor availability is inversely associated with novelty-seeking traits in humans. J Neurosci 28:14372–14378. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Khan ZU, Mrzljak L, Gutierrez A, de la Calle A, Goldman-Rakic PS (1998) Prominence of the dopamine D2 short isoform in dopaminergic pathways. Proc Natl Acad Sci 95:7731–7736. CrossRefPubMedGoogle Scholar
  11. 11.
    Lindgren N, Usiello A, Goiny M, Haycock J, Erbs E, Greengard P, Hokfelt T, Borrelli E et al (2003) Distinct roles of dopamine D2L and D2S receptor isoforms in the regulation of protein phosphorylation at presynaptic and postsynaptic sites. Proc Natl Acad Sci U S A 100:4305–4309. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Tisch S, Silberstein P, Limousin-Dowsey P, Jahanshahi M (2004) The basal ganglia: anatomy, physiology, and pharmacology. Psychiatr Clin North Am 27:757–799. CrossRefPubMedGoogle Scholar
  13. 13.
    Bertolino A, Fazio L, Caforio G, Blasi G, Rampino A, Romano R, di Giorgio A, Taurisano P et al (2009) Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia. Brain 132:417–425. CrossRefPubMedGoogle Scholar
  14. 14.
    Usiello A, Baik J-H, Rougé-Pont F, Picetti R, Dierich A, LeMeur M, Piazza PV, Borrelli E (2000) Distinct functions of the two isoforms of dopamine D2 receptors. Nature 408:199–203. CrossRefPubMedGoogle Scholar
  15. 15.
    Centonze D, Gubellini P, Usiello A, Rossi S, Tscherter A, Bracci E, Erbs E, Tognazzi N et al (2004) Differential contribution of dopamine D2S and D2L receptors in the modulation of glutamate and GABA transmission in the striatum. Neuroscience 129:157–166. CrossRefPubMedGoogle Scholar
  16. 16.
    Stokes PRA, Shotbolt P, Mehta MA, Turkheimer E, Benecke A, Copeland C, Turkheimer FE, Lingford-Hughes AR et al (2013) Nature or nurture? Determining the heritability of human striatal dopamine function: an [18F]-DOPA PET study. Neuropsychopharmacology 38:485–491. CrossRefPubMedGoogle Scholar
  17. 17.
    Borg J, Cervenka S, Kuja-Halkola R, Matheson GJ, Jönsson EG, Lichtenstein P, Henningsson S, Ichimiya T et al (2016) Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain. Mol Psychiatry 21:1077–1084. CrossRefPubMedGoogle Scholar
  18. 18.
    Gluskin BS, Mickey BJ (2016) Genetic variation and dopamine D2 receptor availability: a systematic review and meta-analysis of human in vivo molecular imaging studies. Transl Psychiatry 6:e747. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Zhang Y, Bertolino A, Fazio L, Blasi G, Rampino A, Romano R, Lee MLT, Xiao T et al (2007) Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc Natl Acad Sci 104:20552–20557. CrossRefPubMedGoogle Scholar
  20. 20.
    Blasi G, Lo Bianco L, Taurisano P, Gelao B, Romano R, Fazio L, Papazacharias A, di Giorgio A 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. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Taurisano P, Romano R, Mancini M, Giorgio AD, Antonucci LA, Fazio L, Rampino A, Quarto T et al (2014) Prefronto-striatal physiology is associated with schizotypy and is modulated by a functional variant of DRD2. Front Behav Neurosci 8(235).
  22. 22.
    Clarke T, Weiss ARD, Ferarro TN et al (2014) The dopamine receptor D2 (DRD2) SNP rs1076560 is associated with opioid addiction. Ann Hum Genet 78:33–39. CrossRefPubMedGoogle Scholar
  23. 23.
    Moyer RA, Wang D, Papp AC, Smith RM, Duque L, Mash DC, Sadee W (2010) Intronic polymorphisms affecting alternative splicing of human dopamine D2 receptor are associated with cocaine abuse. Neuropsychopharmacology 36:753–762. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Blasi G, Napolitano F, Ursini G, Taurisano P, Romano R, Caforio G, Fazio L, Gelao B et al (2011) DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia. Proc Natl Acad Sci U S A 108:1158–1163. CrossRefPubMedGoogle Scholar
  25. 25.
    Miller NS, Chou KL, Bohnen NI, Müller MLTM, Seidler RD (2018) Dopaminergic polymorphisms associated with medication responsiveness of gait in Parkinson’s disease. Parkinsonism Relat Disord 48:54–60. CrossRefPubMedGoogle Scholar
  26. 26.
    Masellis M, Collinson S, Freeman N, Tampakeras M, Levy J, Tchelet A, Eyal E, Berkovich E et al (2016) Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson’s disease: a pharmacogenetic study. Brain 139:2050–2062. CrossRefPubMedGoogle Scholar
  27. 27.
    Fazio L, Blasi G, Taurisano P, Papazacharias A, Romano R, Gelao B, Ursini G, Quarto T et al (2011) D2 receptor genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans. Neuroimage 54:2915–2921. CrossRefPubMedGoogle Scholar
  28. 28.
    Bertolino A, Taurisano P, Pisciotta NM, Blasi G, Fazio L, Romano R, Gelao B, Bianco LL et al (2010) Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance. PLoS One 5:e9348. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Abi-Jaoude E, Segura B, Obeso I, Cho SS, Houle S, Lang AE, Rusjan P, Sandor P et al (2015) Similar striatal D2/D3 dopamine receptor availability in adults with Tourette syndrome compared with healthy controls: a [11C]-(+)-PHNO and [11C] raclopride positron emission tomography imaging study. Hum Brain Mapp 36:2592–2601. CrossRefPubMedGoogle Scholar
  30. 30.
    Cho SS, Koshimori Y, Aminian K, Obeso I, Rusjan P, Lang AE, Daskalakis ZJ, Houle S et al (2015) Investing in the future: stimulation of the medial prefrontal cortex reduces discounting of delayed rewards. Neuropsychopharmacology 40:546–553. CrossRefPubMedGoogle Scholar
  31. 31.
    Freedman SB, Patel S, Marwood R et al (1994) Expression and pharmacological characterization of the human D3 dopamine receptor. J Pharmacol Exp Ther 268:417–426PubMedGoogle Scholar
  32. 32.
    Narendran R, Slifstein M, Guillin O et al (2006) Dopamine (D2/3) receptor agonist positron emission tomography radiotracer [11C]-(+)-PHNO is a D3 receptor preferring agonist in vivo. Synapse 61:790–794. CrossRefGoogle Scholar
  33. 33.
    Willeit M, Ginovart N, Kapur S, Houle S, Hussey D, Seeman P, Wilson AA (2006) High-affinity states of human brain dopamine D2/3 receptors imaged by the agonist [11C]-(+)-PHNO. Biol Psychiatry 59:389–394. CrossRefPubMedGoogle Scholar
  34. 34.
    Graff-Guerrero A, Willeit M, Ginovart N, Mamo D, Mizrahi R, Rusjan P, Vitcu I, Seeman P et al (2008) Brain region binding of the D2/3 agonist [11C]-(+)- PHNO and the D2/3 antagonist [11C] raclopride in healthy humans. Hum Brain Mapp 29:400–410. CrossRefPubMedGoogle Scholar
  35. 35.
    Wilson AA, McCormick P, Kapur S, Willeit M, Garcia A, Hussey D, Houle S, Seeman P et al (2005) Radiosynthesis and evaluation of [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol as a potential radiotracer for in vivo imaging of the dopamine D2 high-affinity state with positron emission tomography. J Med Chem 48:4153–4160. CrossRefPubMedGoogle Scholar
  36. 36.
    Rusjan P, Mamo D, Ginovart N, Hussey D, Vitcu I, Yasuno F, Tetsuya S, Houle S et al (2006) An automated method for the extraction of regional data from PET images. Psychiatry Res Neuroimaging 147:79–89. CrossRefGoogle Scholar
  37. 37.
    Studholme C, Hill DL, Hawkes DJ (1997) Automated three-dimensional registration of magnetic resonance and positron emission tomography brain images by multiresolution optimization of voxel similarity measures. Med Phys 24:25–35. CrossRefPubMedGoogle Scholar
  38. 38.
    Wu Y, Carson RE (2002) Noise reduction in the simplified reference tissue model for neuroreceptor functional imaging. J Cereb Blood Flow Metab 22:1440–1452. CrossRefPubMedGoogle Scholar
  39. 39.
    Ginovart N, Willeit M, Rusjan P, Graff A, Bloomfield PM, Houle S, Kapur S, Wilson AA (2007) Positron emission tomography quantification of [11C]-(+)-PHNO binding in the human brain. J Cereb Blood Flow Metab 27:857–871. CrossRefPubMedGoogle Scholar
  40. 40.
    Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR, Huang Y, Simpson N et al (2001) Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 21:1034–1057. CrossRefPubMedGoogle Scholar
  41. 41.
    Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH (2003) An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 19:1233–1239. CrossRefPubMedGoogle Scholar
  42. 42.
    Laakso A, Vilkman H, Bergman J, Haaparanta M, Solin O, Syvälahti E, Salokangas RKR, Hietala J (2002) Sex differences in striatal presynaptic dopamine synthesis capacity in healthy subjects. Biol Psychiatry 52:759–763CrossRefGoogle Scholar
  43. 43.
    Munro CA, McCaul ME, Wong DF et al (2006) Sex differences in striatal dopamine release in healthy adults. Biol Psychiatry 59:966–974. CrossRefPubMedGoogle Scholar
  44. 44.
    Caravaggio F, Raitsin S, Gerretsen P, Nakajima S, Wilson A, Graff-Guerrero A (2015) Ventral striatum binding of a dopamine D2/3 receptor agonist but not antagonist predicts normal body mass index. Biol Psychiatry 77:196–202. CrossRefPubMedGoogle Scholar
  45. 45.
    Caravaggio F, Ku Chung J, Plitman E, Boileau I, Gerretsen P, Kim J, Iwata Y, Patel R et al (2017) The relationship between subcortical brain volume and striatal dopamine D2/3 receptor availability in healthy humans assessed with [11C]-raclopride and [11C]-(+)-PHNO PET. Hum Brain Mapp 38:5519–5534. CrossRefPubMedGoogle Scholar
  46. 46.
    George SR, Watanabe M, Di Paolo T et al (1985) The functional state of the dopamine receptor in the anterior pituitary is in the high affinity form. Endocrinology 117:690–697. CrossRefPubMedGoogle Scholar
  47. 47.
    Seeman P, Tallerico T, Ko F et al (2002) Amphetamine-sensitized animals show a marked increase in dopamine D2 high receptors occupied by endogenous dopamine, even in the absence of acute challenges. Synapse 46:235–239. CrossRefPubMedGoogle Scholar
  48. 48.
    Leff P (1995) The two-state model of receptor activation. Trends Pharmacol Sci 16:89–97CrossRefGoogle Scholar
  49. 49.
    Leff P, Scaramellini C, Law C, McKechnie K (1997) A three-state receptor model of agonist action. Trends Pharmacol Sci 18:355–362CrossRefGoogle Scholar
  50. 50.
    Boileau I, Payer D, Houle S, Behzadi A, Rusjan PM, Tong J, Wilkins D, Selby P et al (2012) Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-Hexahydro-Naphtho-Oxazin in methamphetamine Polydrug users: a positron emission tomography study. J Neurosci 32:1353–1359. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Sambataro F, Fazio L, Taurisano P, Gelao B, Porcelli A, Mancini M, Sinibaldi L, Ursini G et al (2013) DRD2 genotype-based variation of default mode network activity and of its relationship with striatal DAT binding. Schizophr Bull 39:206–216. CrossRefPubMedGoogle Scholar
  52. 52.
    Caravaggio F, Nakajima S, Borlido C, Remington G, Gerretsen P, Wilson A, Houle S, Menon M et al (2014) Estimating endogenous dopamine levels at D2 and D3 receptors in humans using the agonist radiotracer [11C]-(+)-PHNO. Neuropsychopharmacology 39:2769–2776. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Nakajima S, Caravaggio F, Boileau I, Chung JK, Plitman E, Gerretsen P, Wilson AA, Houle S et al (2015) Lack of age-dependent decrease in dopamine D3 receptor availability: a [(11)C]-(+)-PHNO and [(11)C]-raclopride positron emission tomography study. J Cereb Blood Flow Metab 35:1812–1818. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Watanabe K, Kita T, Kita H (2009) Presynaptic actions of D2-like receptors in the rat cortico-striato-globus pallidus disynaptic connection in vitro. J Neurophysiol 101:665–671. CrossRefPubMedGoogle Scholar
  55. 55.
    Seeman P, Mccormick PN, Kapur S (2007) Increased dopamine D2High receptors in amphetamine-sensitized rats, measured by the agonist [3H](+)PHNO. Synapse 61:263–267. CrossRefPubMedGoogle Scholar
  56. 56.
    Valli M, Mihaescu A, Strafella AP (2017) Imaging behavioural complications of Parkinson’s disease. Brain Imaging Behav:1–10.
  57. 57.
    Bortolon C, Macgregor A, Capdevielle D, Raffard S (2017) Apathy in schizophrenia: a review of neuropsychological and neuroanatomical studies. Neuropsychologia. 118:22–33. CrossRefPubMedGoogle Scholar
  58. 58.
    Pagonabarraga J, Kulisevsky J, Strafella AP, Krack P (2015) Apathy in Parkinson’s disease: clinical features, neural substrates, diagnosis, and treatment. Lancet Neurol 14:518–531. CrossRefPubMedGoogle Scholar
  59. 59.
    Tziortzi AC, Searle GE, Tzimopoulou S, Salinas C, Beaver JD, Jenkinson M, Laruelle M, Rabiner EA et al (2011) Imaging dopamine receptors in humans with [11C]-(+)-PHNO: Dissection of D3 signal and anatomy. Neuroimage 54:264–277. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Mikaeel Valli
    • 1
    • 2
    • 3
  • Sang Soo Cho
    • 1
    • 2
  • Mario Masellis
    • 4
  • Robert Chen
    • 2
    • 5
  • Pablo Rusjan
    • 1
  • Jinhee Kim
    • 1
    • 2
  • Yuko Koshimori
    • 1
    • 6
  • Alexander Mihaescu
    • 1
    • 2
    • 3
  • Antonio P. Strafella
    • 1
    • 2
    • 3
    • 5
    Email author
  1. 1.Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental HealthUniversity of TorontoTorontoCanada
  2. 2.Division of Brain, Imaging and Behaviour – Systems Neuroscience, Krembil Research Institute, UHNUniversity of TorontoTorontoCanada
  3. 3.Institute of Medical ScienceUniversity of TorontoTorontoCanada
  4. 4.Hurvitz Brain Sciences ProgramSunnybrook Research InstituteTorontoCanada
  5. 5.Morton and Gloria Shulman Movement Disorder Unit & E.J. Safra Parkinson Disease Program, Neurology Division, Dept. of Medicine, Toronto Western Hospital, UHNUniversity of TorontoTorontoCanada
  6. 6.Music and Health Research Collaboratory (MaRC), Faculty of MusicUniversity of TorontoTorontoCanada

Personalised recommendations