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Extreme phenotypic diversity in operant response to intravenous cocaine or saline infusion in the hybrid mouse diversity panel. | LitMetric

AI Article Synopsis

  • Cocaine self-administration is affected by genetics, with specific genetic variants still unidentified that impact individual differences in cocaine use among lab animals.
  • In a study using 84 different mouse strains, researchers found significant heritability in cocaine use, with some strains exhibiting high levels of intake while others showed none, indicating genetic variation influences this behavior.
  • Genome-wide association studies (GWAS) identified key genetic loci related to cocaine use on Chromosomes 3 and 14, allowing the identification of potential genetic factors that could help explain variations in cocaine reinforcement and addiction risk.

Article Abstract

Cocaine self-administration is a complexly determined trait, with a substantial proportion of individual differences being determined by genetic variation. However, the relevant genetic variants that drive heritable differences in cocaine use remain undiscovered. Cocaine intravenous self-administration (IVSA) procedures in laboratory animals provide opportunities to prospectively investigate neurogenetic influences on the acquisition of voluntary cocaine use. Here, we provide information on cocaine (or saline-as a control) IVSA in 84 members of the hybrid mouse diversity panel (HMDP), an array of genetically distinct classical or recombinant inbred strains. We found cocaine IVSA to be substantially heritable in this population, with strain-level intake ranging for near 0 to >25 mg/kg/session. Though saline IVSA was also found to be heritable, a modest genetic correlation between cocaine and saline IVSA indicates that operant responding for the cocaine reinforcer was influenced, at least in part, by unique genetic variants. Genome-wide association studies (GWAS) of infusions earned in cocaine and saline groups revealed significant quantitative trait loci (QTL) on Chromosomes 3 and 14 for cocaine, but not saline, IVSA. Positional candidates were further prioritized through use of bulk RNA sequencing data that revealed genes with cis-eQTL and genetic correlation to number of infusions. Additionally, these data identify reference strains with extreme cocaine IVSA phenotypes, revealing them as polygenic models of risk and resilience to cocaine reinforcement. This work is part of an ongoing effort to characterize genetic variation that moderates cocaine IVSA that may, in turn, provide a more comprehensive understanding of cocaine risk genetics and neurobiology.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870574PMC
http://dx.doi.org/10.1111/adb.13162DOI Listing

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