Modulation of oxycodone oral self-administration by the gut microbiome

Introduction: While emphasis on achieving a better understanding of substance use disorders has naturally focused on intrinsic central nervous system (CNS) mechanisms, it is conceivable that signals from outside of the CNS could play a role in abuse of oxycodone and other prescription opiates as interoceptive cues. Given that emerging evidence suggests a role of the gut microbiome in the actions of cocaine, alcohol, nicotine stimulants and hallucinogens, it is possible that it could also be involved in oxycodone responses. Therefore, the objective of this study was to determine the influence of the gut microbiome on oxycodone oral self-administration (SA). Hypothesis: The absence or depletion of a gut microbiome will alter the rewarding properties of oxycodone, such that CONV mice will exhibit significantly higher oxycodone SA whereas GF mice will show reduced consumption. METHODOLOGY: Adult C56BL6 males and females (8 weeks old) were subjected to oxycodone oral SA (1 mg/ml) using a two-bottle choice (drug and water) for 5 days and their intake was measured daily. Two experiments were carried out: 1. GF and conventionally raised (CONV) mice were compared for their oxycodone intake; 2. CONV mice treated with water or with the antibiotic ceftriaxone were compared for their oxycodone SA. Fecal samples were collected before and after oxycodone intake and the microbiome profile was evaluated using 16S rRNA sequencing. Striatal samples from CONV mice treated with oxycodone and controls were subjected to proteomics analyses. Results: Experiment 1 shows that GF mice exhibited a significantly higher oxycodone SA than CONV mice (Days of oxycodone, GF status, and the interaction between these two factors, were significant using a mixed effect model). While both GF males and females show a greater oxycodone SA, GF females displayed an enhanced drug intake response compared to CONV females (F (1, 20) = 65.28, p < 0.0001). Experiment 2 shows that depletion of the gut microbiome with ceftriaxone reduced oral oxycodone SA (Days of oxycodone, ceftriaxone/oxycodone treatment, and these two factors interaction, were significant using a mixed effect model). In addition, oxycodone SA significantly altered the bacterial composition (i.e., β-diversity using Jaccard) of the gut (p< 0.0001, NP MANOVA) by comparison to controls. Proteomics analyses of striatum of mice undergoing oxycodone SA showed an upregulation of proteins involved in responses to cellular stress, cytoskeleton remodeling, mitochondrial function, and energy metabolism, compared to mice receiving water instead of drug. Conclusions: Although our hypothesis about the regulation of the microbiome in response to oxycodone intake was partially confirmed, the effects observed were opposite to what we had anticipated. The absence or depletion of the gut microbiome increases oxycodone SA, with females exhibiting greater responses. This research was supported by departmental startup funds provided by WSU Department of Physiology to MAP. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.