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Addiction-related genes in gambling disorders: new insights from parallel human and pre-clinical models

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Abstract

Neurobiological research supports the characterization of disordered gambling (DG) as a behavioral addiction. Recently, an animal model of gambling behavior was developed (rat gambling task, rGT), expanding the available tools to investigate DG neurobiology. We investigated whether rGT performance and associated risk gene expression in the rat’s brain could provide cross-translational understanding of the neuromolecular mechanisms of addiction in DG. We genotyped tagSNPs (single-nucleotide polymorphisms) in 38 addiction-related genes in 400 DG and 345 non-DG subjects. Genes with P<0.1 in the human association analyses were selected to be investigated in the animal arm to determine whether their mRNA expression in rats was associated with the rat’s performance on the rGT. In humans, DG was significantly associated with tagSNPs in DRD3 (rs167771) and CAMK2D (rs3815072). Our results suggest that age and gender might moderate the association between CAMK2D and DG. Moderation effects could not be investigated due to sample power. In the animal arm, only the association between rGT performance and Drd3 expression remained significant after Bonferroni correction for 59 brain regions. As male rats were used, gender effects could not be investigated. Our results corroborate previous findings reporting the involvement of DRD3 receptor in addictions. To our knowledge, the use of human genetics, pre-clinical models and gene expression as a cross-translation paradigm has not previously been attempted in the field of addictions. The cross-validation of human findings in animal models is crucial for improving the translation of basic research into clinical treatments, which could accelerate neurobiological and pharmacological investigations in addictions.

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Acknowledgements

We thank the Ontario Problem Gambling Research Centre and the Alberta Gaming Research Institute for funding our research. We thank all research staff involved in the assessment of subjects and monitoring of animals. We thank Natalie Freeman, Sajid Shaikh and Maria Tampakeras for the preparation of DNA samples and genotyping. This study was funded through grants received from the Ontario Problem Gambling Research Centre (OPGRC #2632 and #2277) and from the Alberta Gaming Research Institute (AGRI# 73-4142). Ms Aleksandrova was partially funded through a Master’s Studentship from the Ontario Problem Gambling Research Centre.

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The authors declare that Dr Kennedy has received honorarium from Roche Pharma, Lilly, and Novartis in the last three years.

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Lobo, D., Aleksandrova, L., Knight, J. et al. Addiction-related genes in gambling disorders: new insights from parallel human and pre-clinical models. Mol Psychiatry 20, 1002–1010 (2015). https://doi.org/10.1038/mp.2014.113

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