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

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Abstract

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.

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Acknowledgments

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.

Funding

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.

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Authors and Affiliations

  1. Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada

    Mikaeel Valli, Sang Soo Cho, Pablo Rusjan, Jinhee Kim, Yuko Koshimori, Alexander Mihaescu & Antonio P. Strafella

  2. Division of Brain, Imaging and Behaviour – Systems Neuroscience, Krembil Research Institute, UHN, University of Toronto, Toronto, Ontario, Canada

    Mikaeel Valli, Sang Soo Cho, Robert Chen, Jinhee Kim, Alexander Mihaescu & Antonio P. Strafella

  3. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    Mikaeel Valli, Alexander Mihaescu & Antonio P. Strafella

  4. Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada

    Mario Masellis

  5. Morton and Gloria Shulman Movement Disorder Unit & E.J. Safra Parkinson Disease Program, Neurology Division, Dept. of Medicine, Toronto Western Hospital, UHN, University of Toronto, Toronto, Ontario, Canada

    Robert Chen & Antonio P. Strafella

  6. Music and Health Research Collaboratory (MaRC), Faculty of Music, University of Toronto, Toronto, Ontario, Canada

    Yuko Koshimori

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  1. Mikaeel Valli
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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

Corresponding author

Correspondence to Antonio P. Strafella.

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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.

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Valli, M., Cho, S.S., Masellis, M. et al. DRD2 Genotype-Based Variants Modulates D2 Receptor Distribution in Ventral Striatum. Mol Neurobiol 56, 6512–6520 (2019). https://doi.org/10.1007/s12035-019-1543-0

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