title: Addiction-related genes in gambling disorders: new insights from parallel human and pre-clinical models.
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.
authors.affiliation: 1] Department of Psychiatry, University of Toronto, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: D S S
authors.initials: DS
authors.lastname: Lobo
authors.affiliation: 1] Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Aleksandrova
authors.affiliation: 1] Department of Psychiatry, University of Toronto, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Knight
authors.affiliation: Mental Health Commission of Canada, Calgary, AB, Canada.
authors.forename: D M
authors.initials: DM
authors.lastname: Casey
authors.affiliation: Division of Addiction, Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
authors.forename: N
authors.initials: N
authors.lastname: el-Guebaly
authors.affiliation: 1] Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Departments of Pharmacology and Toxicology, Psychiatry, and Psychology, University of Toronto, Toronto, ON, Canada.
authors.forename: J N
authors.initials: JN
authors.lastname: Nobrega
authors.affiliation: 1] Department of Psychiatry, University of Toronto, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: J L
authors.initials: JL
authors.lastname: Kennedy
mesh_terms: D000328:Adult; D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005715:Gambling / Q000235:genetics* / Q000378:metabolism; D005717:Games, Experimental; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000235:genetics / Q000378:metabolism; D012306:Risk
chemical_list: C493593:DRD3 protein, human; C493595:Drd3 protein, rat; D012333:RNA, Messenger; D050637:Receptors, Dopamine D3; C517660:CAMK2D protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2