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Updated: Sep 6, 2025

Intracerebroventricular Delivery of Gut-Derived Microbial Metabolites in Freely Moving Mice
Published on: June 2, 2022
Dose- and Sex-Dependent Bidirectional Relationship between Intravenous Fentanyl Self-Administration and Gut
Michelle Ren1, Shahrdad Lotfipour1,2,3
1Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California Irvine, Irvine, CA 92697, USA.
Abstract:
Gut bacteria influence neural circuits in addiction-related behaviors. Given the association between opioid use, gastrointestinal distress, and microbial dysbiosis in humans and mice, we test the hypothesis that interactions between gut bacteria and the brain mediate the rewarding and reinforcing properties of fentanyl. We implant rats with intravenous catheters in preparation for fentanyl intravenous self-administration (IVSA) on an escalating schedule of reinforcement to determine factors that influence fentanyl intake, including sex, dose, and gut microbiota. Our data show the impact of fentanyl IVSA on gut microbiota diversity, as well as the role of gut microbiota on fentanyl IVSA, in Sprague Dawley rats in a sex- and dose-dependent manner (n = 10-16/group). We found that the diversity of gut microbiota within females dose-dependently predicts progressive but not fixed ratio schedules of fentanyl IVSA. Depending on sex and fentanyl dose, alpha diversity (richness and evenness measured with Shannon index) is either increased or decreased following fentanyl IVSA and predicts progressive ratio breakpoint. Our findings collectively suggest a role of gut bacteria in drug-related behavior, including motivation and reinforcement. This work provides feasibility for an intravenous fentanyl self-administration model and uncovers potential factors mediating drug use, which may lead to the development of effective addiction interventions.
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