Substance use disorder (SUD) is associated with a cluster of cognitive disturbances that engender vulnerability to ongoing drug seeking and relapse. Two of these endophenotypes, risky decision-making and impulsivity, are amplified in individuals with substance use disorder and are augmented by repeated exposure to illicit drugs. Thus, identifying the genetic factors underlying variability in these traits is critical for early identification and ongoing treatment of SUD-vulnerable individuals. Here, we compared risky decision-making and different facets of impulsivity between two commercially available substrains of inbred Lewis rats (Charles River vs. Envigo). We also performed whole genome sequencing (WGS) to identify genetic variants between strains. We observed differences in risky decision-making and impulsive action, with Lewis rats from Charles River demonstrating both increased preference for risky options in the risky decision-making task and increased premature responses in the Differential Reinforcement of Low Rates of Responding (DRL) task. Interestingly, these phenotypic differences were more pronounced in females than males. Our WGS at ~40X coverage detected a total of ~9,000 polymorphisms between these substrain. Roughly half are located within a single 1.5 Mb region of Chromosome 8, but do not impact any protein coding genes. In contrast the other widely distributed variants are predicted to have moderate or high impact on the function of 38 protein-coding genes. In conclusion, Lewis rat substrains differ significantly in risk-taking and impulsivity but only a small number of easily mapped variants are likely to be causal. Sequencing combined with a reduced complexity cross (RCC) should enable identification of one or more variants underlying multiple complex addiction-relevant traits.
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