Behavioral flexibility, gut microbiome composition, and individual variability in oral oxycodone self-administration

Prescription opioids such as oxycodone have been widely used in the United States and have contributed to the ongoing opioid epidemic. Although many individuals limit their use to prescribed contexts, a subset transitions to misuse and, in some cases, illicit opioid use. Identifying factors associated with variability in opioid intake may improve our understanding of vulnerability to opioid misuse. Here, we examined relationships among behavioral flexibility, gut microbiome composition, and subsequent oxycodone intake using an oral oxycodone self-administration model in male and female Long-Evans rats. Principal component analysis identified patterns of self-administration behavior that differentiated oxycodone-exposed animals from water controls. Among oxycodone-exposed animals, the principal component that contained variables of reinforced behaviors (i.e., active hole responding, reinforcers earned) was positively associated with oxycodone consumption, and hierarchical clustering identified three behavioral profiles distributed along this relationship. Behavioral flexibility, assessed before drug exposure using a contingency degradation task, was negatively associated with subsequent oxycodone intake, although it was not associated with the principal component measure of self-administration behavior. Oral oxycodone exposure was also associated with changes in gut microbiome composition, and analyses identified microbiome features associated with behavioral flexibility and oxycodone intake. Together, these findings demonstrate individual variability in oral oxycodone self-administration and identify behavioral and microbiome measures associated with subsequent drug-taking behavior. These results provide a foundation for future studies examining whether these measures prospectively contribute to vulnerability to opioid misuse.