# A Novel Role of Interpeduncular Nucleus GLP-1Rs in Fentanyl Reinstatement

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2024 · $48,974

## Abstract

Project Summary:
 Fatal opioid overdose is a leading cause of preventable death in the United States, and in 2021 more
than 60% of drug overdose deaths were associated with fentanyl and its analogs. While current pharmacological
treatments for opioid use disorder are effective, stigma and limited access make these medications underutilized
and rates of relapse are still high. Despite the prevalence of illicit fentanyl use, there are very few studies
investigating the neurobiological mechanisms underlying fentanyl seeking. Advancing our understanding of the
neural circuits underlying fentanyl seeking may facilitate the development of novel treatments for fentanyl use
disorder and reduce fentanyl overdose deaths. Recently, we showed that systemic administration of the
glucagon-like peptide-1 receptor (GLP-1R) agonist Exendin-4 (Ex-4) attenuates fentanyl reinstatement, a model
of relapse. However, the neural mechanisms underlying the suppressive effects of Ex-4 on fentanyl seeking are
unclear. Our exciting pilot studies demonstrate that activation of GLP-1Rs in the interpeduncular nucleus (IPN),
a brain region known to regulate the mesolimbic dopamine system, is sufficient to attenuate fentanyl-seeking
behavior during abstinence in male and female rats. Additionally, we discovered µ opioid receptors and GLP-
1Rs expressed on GABAergic neurons that project from the IPN to the laterodorsal tegmental nucleus (LDTg),
a nucleus that sends projections to the VTA and plays an important role in drug seeking and opioid-induced
reward. These results highlight a neural circuit that may mediate the suppressive effects of GLP-1R agonists on
fentanyl seeking. However, the activity of this circuit during fentanyl-seeking behavior has not been investigated.
The goal of this proposal is to determine the impact of acute fentanyl and Ex-4 on neural activity in the GABAergic
IPNàLDTg pathway and the relationship between such activity and fentanyl-seeking behavior. To investigate
the role of the GABAergic IPNàLDTg projection in fentanyl reinstatement, Aim 1 will use in vivo calcium imaging
to characterize the real-time activity of GABAergic IPN projections to the LDTg during fentanyl-seeking behavior.
Aim 2 will determine how Ex-4 pharmacotherapy alters calcium activity of GABAergic IPNàLDTg projections to
reduce fentanyl seeking. Successful completion of these aims will be an important foundation for future studies
investigating the neural basis of fentanyl seeking. Ideally, results from this work will suggest novel therapeutic
avenues for fentanyl use disorder. Completion of this fellowship will achieve the training goals of expanding the
technical expertise of Ms. Herman in addiction neuroscience and facilitate her career goal of becoming a leading
researcher in the neurobiology of substance use disorders.

## Key facts

- **NIH application ID:** 10885915
- **Project number:** 5F31DA058451-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Rachel Jaschik Herman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885915

## Citation

> US National Institutes of Health, RePORTER application 10885915, A Novel Role of Interpeduncular Nucleus GLP-1Rs in Fentanyl Reinstatement (5F31DA058451-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10885915. Licensed CC0.

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