A hindbrain to VTA pathway regulates cocaine-seeking behavior via a glucagon-like peptide-1 dependent mechanism

Vanessa holding a rat model

Students

Faculty

Associate Professor of Nursing and Psychiatry

Project Summary

Special thanks to the Mary L. And Matthew S. Santirocco College Alumni Society Undergraduate Research Grant for allowing me to continue my research journey this summer. In the lab of Dr. Heath Schmidt, where I work as a research assistant, we investigate the neurological underpinnings of drug addiction, with particular attention to the way in which metabolic factors modulate cocaine seeking. To expand upon my CURF-funded research conducted last summer, this year I investigated the role of the endogenous GLP-1 system in regulating cocaine priming-induced reinstatement, an animal model of relapse.

Since cocaine addiction is a prevalent public health problem with no FDA-approved treatments, there is a clear need for novel pharmacotherapies to treat cocaine dependence. Growing evidence suggests that glucagon-like peptide-1 (GLP-1) receptors may serve as potential molecular targets for new drugs aimed at preventing cocaine craving and relapse. GLP-1 is a satiation factor that is produced in the nucleus tractus solitarius (NTS) of the hindbrain. GLP-1 receptors (GLP-1R) are expressed throughout the brain, including the ventral tegmental area (VTA). We have recently shown that infusions of exogenous GLP-1R agonists into the VTA suppress cocaine-seeking behavior. Using a chemogenetic approach, my data from last summer showed that activation of NTS neurons projecting to the VTA attenuated cocaine-seeking behavior. However, the NTS is comprised of heterogenous cell populations. Thus, it is not clear whether our results were due to activation of GLP-expressing neurons in the NTS that project to the VTA. Therefore, the overarching goal of this study was to determine the exact role of endogenous NTS GLP-1-expressing neurons that project to VTA in cocaine reinstatement.

Since GLP-1R agonists infused into the VTA and activation of NTS projections to the VTA both decrease cocaine seeking, we hypothesized that pharmacologically blocking GLP-1Rs in the VTA would prevent the ability of chemogenetic activation of endogenous NTS->VTA circuits to reduce cocaine seeking. We selectively activated NTS projections to the VTA via designer receptors exclusively activated by designer drugs (DREADDs) during cocaine seeking following pretreatment of the GLP-1R antagonist Exendin-9 (Ex-9) in the VTA. Results showed that chemogenetic activation of endogenous NTS to VTA projections significantly attenuated cocaine seeking in a dose dependent manner and the effects may depend on increased GLP-1 signaling in the VTA. Additionally, we validated DREADD viral expression and showed that Dreadds co-localized with both GLP-1 neurons and were activated by CNO. Furthermore, activation of endogenous NTS to VTA circuits in cocaine-experienced rats did not affect food intake and body weight. Taken together these data indicate that increased endogenous GLP-1 signaling in the VTA could attenuate cocaine seeking and suggest that novel therapies targeting this circuit may reduce cocaine craving-induced relapse in human addicts.

It was a really excited opportunity to be able to continue my project from last summer. These promising results will allow me to execute a more encompassing project for independent study in BIBB 399 and 499. Under the mentorship of graduate student Nicole Hernandez, I was able to build upon my lab procedures and techniques that I had already garnered. For example, I improved my proficiency on stereotactic surgeries for viral injections as well as cranial microinjections during treatments.  Pursuing research this summer has not only confirmed my interest in neuroscience, but given me invaluable skills that will aid me as a future physician. Thank you to CURF, Dr. Schmidt, and the entire Schmidt lab for the tremendous experience.