The Collaborative Cross strains and their founders vary widely in cocaine-induced behavioral sensitization

Abstract

Cocaine use and overdose deaths attributed to cocaine have increased significantly in the United States in the last 10 years. Despite the prevalence of cocaine use disorder (CUD) and the personal and societal problems it presents, there are currently no approved pharmaceutical treatments. The absence of treatment options is due, in part, to our lack of knowledge about the etiology of CUDs. There is ample evidence that genetics plays a role in increasing CUD risk but thus far, very few risk genes have been identified in human studies. Genetic studies in mice have been extremely useful for identifying genetic loci and genes, but have been limited to very few genetic backgrounds, leaving substantial phenotypic and genetic diversity unexplored. Herein we report the measurement of cocaine-induced behavioral sensitization using a 19-day protocol that captures baseline locomotor activity, acute locomotor response to cocaine and locomotor sensitization across 5 exposures to the drug. These behaviors were measured in 51 genetically diverse yet tractable Collaborative Cross (CC) strains along with their inbred founder strains. The CC was generated by crossing 8 genetically diverse inbred strains such that each inbred CC strain has genetic contributions from each of the founder strains. Inbred CC mice are infinitely reproducible and provide a stable, yet diverse genetic platform on which to study the genetic architecture and genetic correlations among phenotypes. We have identified significant differences in cocaine locomotor sensitivity and behavioral sensitization across the panel of CC strains and their founders. We have established relationships among cocaine sensitization behaviors and identified extreme responding strains that can be used in future studies aimed at understanding the genetic, biological and pharmacological mechanisms that drive addiction-related behaviors. Finally, we have determined that these behaviors exhibit relatively robust heritability making them amenable to future genetic mapping studies to identify addiction risk genes and genetic pathways that can be studied as potential targets for the development of novel therapeutics.

Genetic pathways regulating the longitudinal acquisition of cocaine self-administration in inbred and recombinant inbred mice

“…Further evidence for a genetic basis of cocaine use was the observation that an acute dose of the drug caused significant differences in locomotor activity across 45 inbred mouse strains (Wiltshire et al, 2015). Divergence in sensitization to cocaine was also found using 51 genetically diverse collaborative cross strains and their inbred founders (Schoenrock et al, 2022). An elegant study using two closely related substrains of the C57BL/6 mouse strain revealed that a missense mutation in Cyfip2 results in altered sensitization to cocaine (Kumar et al, 2013).…”