The microbial community dynamics of cocaine sensitization in two behaviorally divergent strains of collaborative cross mice

The gut microbiome-brain axis is increasingly recognized as an important pathway in regulation of cocaine addiction. Microbial products produced in the murine gut have been shown to affect striatal gene expression, and depletion of the microbiome by antibiotic treatment alters cocaine-induced behavioral sensitization in C57BL/6J male mice. Cocaine-induced behavioral sensitization is correlated with drug self-administration behavior, therefore, is a predictor of addiction vulnerability. Here we profile the composition of the naïve microbiome and its response to cocaine sensitization in two Collaborative Cross (CC) strains. These strains display extremely divergent behavioral responses to cocaine sensitization. A high-responding strain, CC004/TauUncJ (CC04), has a gut microbiome that contains a greater amount of Lactobacillus than the cocaine-nonresponsive strain CC041/TauUncJ (CC41). The gut microbiome of CC41 is characterized by an abundance of Eisenbergella, Robinsonella and Ruminococcus. In response to cocaine, CC04 has an increased Barnsiella population, while the gut microbiome of CC41 displays no significant changes. PICRUSt functional analysis of the functional potential of the gut microbiome in CC04 shows a significant number of Gut-Brain Modules altered after exposure to cocaine, specifically those encoding for tryptophan synthesis, glutamine metabolism, and menaquinone synthesis (vitamin K2). Depletion of the microbiome by antibiotic treatment revealed a sex-specific altered cocaine-sensitization response to antibiotics in female mice from CC04 that was not observed in male CC04 or either sex of CC41. Together these data suggest a complex relationship between host genetics, microbiome composition and cocaine sensitization behavior. FUNDING U01DA043809 to JAB, GMW P50DA039841 to EJC