Skip to main content
eScholarship
Open Access Publications from the University of California

UC Irvine

UC Irvine Electronic Theses and Dissertations bannerUC Irvine

The bidirectional relationship between gut bacteria and intravenous fentanyl self-administration

Abstract

The United States is currently experiencing its worst drug crisis, which is largely driven by opioid addiction and primarily due to fentanyl. It is therefore necessary to investigate the mechanisms mediating fentanyl's rewarding and reinforcing properties to contribute to the development of successful treatment strategies. Gut bacteria communicate with the brain, and vice versa, via the gut-brain axis to regulate brain function, mood, and behavior. Addiction is a chronic brain disorder that alters circuitry involved in reward, stress, learning, and motivation, all of which have a bidirectional influence between their associated behaviors and gut bacteria. Given the associations between opioid use, gastrointestinal distress, and microbial dysbiosis in humans and rodents, I tested the hypothesis that interactions between gut bacteria and the brain mediate the reinforcing and motivational properties of fentanyl. In this dissertation, I present my work that supports a bidirectional relationship between gut bacteria and fentanyl intravenous self-administration (IVSA) in Sprague Dawley rats. In the following studies, I implanted rats with intravenous catheters in preparation for fentanyl IVSA on an escalating schedule of reinforcement and analyzed gut microbiota by sequencing bacterial DNA from rat fecal samples. I demonstrate that based on sex and fentanyl dose, the diversity of gut bacteria is either increased or decreased following fentanyl IVSA and predicts progressive ratio breakpoint, a measure of motivation. Further, I show that depletion of gut bacteria via prolonged oral antibiotic treatment enhances fentanyl IVSA, and restoration of microbial metabolites with short-chain fatty acid administration decreases fentanyl IVSA back to controls at higher fixed ratio schedules of reinforcement. My findings highlight an important relationship between the knockdown and rescue of gut bacterial metabolites and fentanyl self-administration in adult rats, which provides support for a relationship between gut microbiota and opioid use. Further work in this area may lead to effective, targeted treatment interventions in opioid-related disorders.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View