# The role of central GLP-1 receptors in animal models of cocaine addiction

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $415,101

## Abstract

Project Summary
Cocaine addiction continues to be a significant public health problem for which there are currently no effective
FDA-approved pharmacological treatments. Therefore, there is a clear need to identify novel neural
mechanisms underlying cocaine craving and relapse in order to develop new pharmacotherapies to treat this
disease. We have recently shown that central glucagon-like peptide-1 receptors (GLP-1Rs) play an important
role in cocaine reinforcement and the reinstatement of cocaine seeking, an animal model of relapse.
Specifically, we identified behaviorally relevant doses of a GLP-1R agonist that selectively reduced cocaine
seeking and did not produce adverse effects commonly associated with these medications in humans and
rodents. While these exciting findings clearly highlight a novel neuroendocrine mechanism that could be
targeted to prevent cocaine craving-induced relapse, the neural mechanisms mediating the effects of GLP-1R
agonists on cocaine seeking remain unclear. One goal of this proposal is to fill the gaps in our understanding of
the central GLP-1 circuits regulating cocaine seeking. In Aim 1, we will extend this circuitry to include the
lateral dorsal tegmental area (LDTg) and amygdala, two nuclei known to play critical roles in the reinstatement
of cocaine seeking. We will also use a systems neuroscience approach to phenotype GLP-1R-expressing cells
and identify their targets. Findings from these studies will provide the first comprehensive neuroanatomical
map of GLP-1 circuits in the rat brain. Our pilot studies also reveal that GLP-1Rs are expressed on astrocytes
and neurons in the rat brain. Using viral-mediated gene delivery and fiber photometry approaches in Aim 2, we
will determine if reduced GLP-1R expression selectively on astrocytes and/or neurons prevents the
suppressive effects of a GLP-1R agonist on cocaine seeking. In addition, we will investigate cell-type specific
effects of GLP-1R activation on astrocyte activity and neuronal function during the reinstatement of cocaine
seeking. We have also discovered that cocaine self-administration and subsequent abstinence dynamically
regulate expression of endogenous preproglucagon (PPG), the gene that encodes GLP-1, in the hindbrain.
These provocative findings suggest that reduced endogenous PPG expression during abstinence may facilitate
cocaine seeking. However, the molecular and epigenetic mechanisms by which cocaine exposure regulates
PPG expression are unknown. We will use chromatin immunoprecipitation (ChIP) methods in Aim 3 to identify
the histone posttranslational modifications (PTMs) associated with reduced PPG transcription in the hindbrain.
We will also identify transcription factors that regulate cocaine-induced changes in PPG mRNA expression.
Together, these studies will provide new mechanistic insights into how cocaine exposure influences
endogenous central GLP-1 signaling and highlight molecular substrates that could serve as targets for novel
m...

## Key facts

- **NIH application ID:** 9988387
- **Project number:** 5R01DA037897-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** HEATH D SCHMIDT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $415,101
- **Award type:** 5
- **Project period:** 2015-03-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988387

## Citation

> US National Institutes of Health, RePORTER application 9988387, The role of central GLP-1 receptors in animal models of cocaine addiction (5R01DA037897-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9988387. Licensed CC0.

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