Behavioral and Circuit-Level Insights into GLP-1 Receptor Agonist-Mediated Reduction of Drug Seeking Rachel Herman

Format:

Book

Thesis/Dissertation

Author/Creator:

Herman, Rachel, author.

Contributor:

University of Pennsylvania. Neuroscience., degree granting institution.

Language:

English

Subjects (All):

0317.

0419.

0622.

Local Subjects:

0317.

0419.

0622.

Physical Description:

1 electronic resource (211 pages)

Contained In:

Dissertations Abstracts International 87-09B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2025

Language Note:

English

Summary:

Opioid overdose remains a leading cause of preventable death in the United States, and synthetic opioids like fentanyl drive the majority of these fatalities. Although FDA-approved treatments for opioid use disorder (OUD) are effective, they remain underutilized due to pharmacological constraints and stigma associated with their action at the mu opioid receptor (MOR). Identifying alternative OUD therapies that bypass MOR signaling could improve access to treatment and ultimately reduce opioid use and overdose. Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as a promising class of therapeutics for treating substance use disorders. Notably, these compounds reduce opioid seeking without directly engaging the MOR. However, the neural mechanisms mediating this effect remain unclear. The research presented in this dissertation identifies the interpeduncular nucleus, a midbrain region important for reward, avoidance, and anxiety, as a critical site through which GLP-1R agonists suppress fentanyl seeking. We showed that direct activation of GLP-1Rs within the IPN attenuated opioid-seeking behavior during abstinence and produced sex-specific anxiolytic effects in fentanyl-experienced rats. Using molecular and in vivo imaging approaches, we demonstrated that GLP-1Rs are expressed on GABAergic neurons in the IPN and that the GLP-1R agonist Exendin-4 (Ex-4) increased Ca2+ dynamics in these neurons during fentanyl seeking. Finally, through anatomical tracing and chemogenetic and pharmacological manipulations, we identified a GLP-1R-expressing inhibitory IPN-laterodorsal tegmental nucleus (LDTg) circuit that is necessary for the suppressive effects of Ex-4 on fentanyl seeking. Together, these findings advance our understanding of how the IPN integrates motivational and affective signals to regulate complex behaviors and further support the therapeutic potential of GLP-1R agonists as novel treatments for opioid use disorder

Notes:

Advisors: Schmidt, Heath D. Committee members: Hayes, Matthew; Blendy, Julie A.; Corder, Gregory F.; Hartwell, Emily

Source: Dissertations Abstracts International, Volume: 87-09, Section: B.

Ph.D. University of Pennsylvania 2025

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798277442258

Access Restriction:

Restricted for use by site license