Spontaneously Hypertensive Rat substrains show differences in premorbid addiction vulnerability traits and cocaine self-administration: Implications for a novel rat reduced complexity cross

• Published in: bioRxiv 2021-03
• Main Authors: Kantak, Kathleen M, Stots, Carissa, Mathieson, Elon, Bryant, Camron D
• Format: Article
• Language: English
• Subjects: Addictions; Animal Behavior and Cognition; Cocaine; Drug abuse; Drug addiction; Drug self-administration; Gene mapping; Genetic diversity; Genetic factors; Heritability; Hypertension; Impulsive behavior; Inbreeding; Phenotypes; Reinforcement; Sucrose
• ISSN: 2692-8205
• DOI: 10.1101/2021.03.06.434216

ABSTRACT Forward genetic mapping of F2 crosses between closely related substrains of inbred rodents - referred to as a reduced complexity cross (RCC) - is a relatively new strategy for accelerating the pace of gene discovery for complex traits, such as drug addiction. RCCs to date were generated in mice, but rats are thought to be optimal for addiction genetic studies. Based on past literature, one inbred Spontaneously Hypertensive Rat substrain, SHR/NCrl, is predicted to exhibit a distinct behavioral profile as it relates to cocaine vulnerability traits relative to another substrain, SHR/NHsd. Direct substrain comparisons are a necessary first step before implementing an RCC. We evaluated a number of premorbid addiction vulnerability traits and cocaine self-administration behaviors using a longitudinal within-subjects design. Trait impulsivity and compulsivity were greater in SHR/NCrl than SHR/NHsd, as were reactivity to sucrose reward, sensitivity to acute psychostimulant effects of cocaine, and cocaine abuse liability studied under fixed-ratio and chained schedules of cocaine self-administration. Trait compulsivity correlated with the acute psychostimulant effects of cocaine, which in turn correlated with cocaine taking under the chained schedule. Trait compulsivity also was the best predictor of cocaine seeking responses. Heritability estimates indicated that 22%-40% of the variances for the above phenotypes can be explained by additive genetic factors, providing sufficient genetic variance to conduct genetic mapping in F2 crosses of SHR/NCrl and SHR/NHsd. These results provide compelling support for using an RCC approach in SHR substrains to uncover candidate genes and variants that are of relevance to cocaine use disorders. Highlights * Closely related SHR substrains have distinct cocaine vulnerability traits * Inhibitory control was poorer in SHR/NCrl than SHR/NHsd * SHR/NCrl were more sucrose reactive and sensitive to acute cocaine than SHR/NHsd * Cocaine abuse liability was greater in SHR/NCrl than SHR/NHsd * SHR substrains can be used in an RCC to uncover cocaine vulnerability genes & variants Competing Interest Statement The authors have declared no competing interest.