Author ORCID Identifier

https://orcid.org/0000-0001-8043-8210

Date Available

12-11-2025

Year of Publication

2025

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Arts and Sciences

Department/School/Program

Psychology

Faculty

Michael T. Bardo

Abstract

Purpose: A hallmark characteristic of opioid use disorder (OUD) is a persons’ ‘loss of control’, which leads to the compulsion to seek and obtain opioids, resulting in increased consumption. This phenomenon is known as ‘escalation of drug intake’. Chronic opioid use causes microglial reactivity and subsequent release of proinflammatory cytokines leading to neuroinflammation, weakening one’s executive control over drug taking and ultimately leading to greater use. Previous research in our laboratory has explored heterogeneity of fentanyl intake in extended access (6-hr) sessions and identified distinct endophenotypes of fentanyl intake. Moreover, we have observed a positive correlation between Treml1 expression in the PFC and mean infusions on the last 3 days of fentanyl self-administration (p < 0.05). Our lab has identified microglia-specific transcripts in rats that escalated fentanyl intake in extended access sessions that we explored in the present study. Thus, it is our hypothesis that daily treatments of PLX 3397 will reduce microglia in the PFC and reduce fentanyl intake in extended access session in both males and females. Additionally, we hypothesize that females will show a greater rate of fentanyl escalation and consequently a greater reduction in of fentanyl self-administration compared to males.

Methods: Male and female Sprague-Dawley rats underwent daily 1-hr acquisition sessions for i.v. fentanyl self-administration (2.5 µg/kg; FR1) for 7 days. Starting experimental day 8, rats received once daily injections of PLX 3397 (25 mg/kg, s.c.) until the end of the study. On experimental days 15-35, rats underwent daily 6-hr escalation sessions. Approximately 20 hr after the last self-administration session, acute symptoms of fentanyl-withdrawal were assessed, and tissue from prefrontal cortex was collected for immunofluorescence and qPCR.

Results: Daily administration of PLX 3397 (25 mg/kg; s.c.) reduced the trajectory of escalation of fentanyl intake in females, but not males. Females displayed a greater reduction in the density of IBA1+ cells in PFC, indicative of less microglia, compared to males. We found a positive association with the density of microglia and fentanyl intake at the end of escalation. Moreover, we identified two differentially expressed transcripts, Ptpro and Runx1, that are expressed on microglia and indicate a protective effect of PLX 3397 against inflammatory responses in the CNS.

Conclusion: These findings provide a foundation for the further exploration of non-neuronal targets for treatment of OUD.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2025.578

Funding Information

This study was supported by the McCarty Dissertation Award, National Institutes of Health R01 DA053070, and National Institutes of Health T32 DA035200.

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