Association of novelty-related behaviors and intravenous cocaine self-administration in Diversity Outbred mice

Rationale: The preference for and reaction to novelty are strongly associated with addiction to cocaine and other drugs. However, the genetic variants and molecular mechanisms underlying these phenomena remain largely unknown. Although the relationship between novelty- and addiction-related traits has been observed in rats, studies in mice have failed to demonstrate this association. New, genetically diverse, high-precision mouse populations including Diversity Outbred (DO) mice provide an opportunity to assess an expanded range of behavioral variation enabling detection of associations of novelty- and addiction-related traits in mice. Methods: To examine the relationship between novelty- and addiction-related traits, male (n∈=∈51) and female (n∈=∈47) DO mice were tested on open field exploration, hole board exploration, and novelty preference followed by intravenous cocaine self-administration (IVSA; ten 2-h sessions of fixed ratio 1 and one 6-h session of progressive ratio). Results: We observed high variation of cocaine IVSA in DO mice with 43 % reaching and 57 % not reaching conventional acquisition criteria. As a group, mice that did not reach these criteria still demonstrated significant lever discrimination. Mice experiencing catheter occlusion or other technical issues (n∈=∈17) were excluded from the analysis. Novelty-related behaviors were positively associated with cocaine IVSA. Multivariate analysis of associations among novelty- and addiction-related traits revealed a large degree of shared variance (45 %). Conclusions: Covariation among cocaine IVSA and novelty-related phenotypes in DO mice indicates that this relationship is amenable to genetic dissection. The high genetic precision and phenotypic diversity in the DO may facilitate discovery of previously undetectable mechanisms underlying predisposition to develop addiction disorders.