Date of Award

Spring 4-20-2023

Embargo Period

4-21-2023

Document Type

Thesis

Degree Name

Master of Biomedical Science

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Jacqueline McGinty

Abstract

Withdrawal from cocaine induces an immediate and powerful negative affective state which is characterized by feelings of agitation and anxiety in humans and anxiety-like behaviors in rodents. It has been hypothesized that the anxiogenic effects associated with cocaine withdrawal play a major role in continued cocaine use and drive relapse to cocaine seeking. The prelimbic (PL) medial prefrontal cortex is not only involved in the processing and regulation of negative emotions such as anxiety but also mediates relapse to cocaine-seeking. Subcortical hubs of the reward system that receive projections from the PL neurons are known to be dysregulated during different stages of cocaine addiction, including withdrawal. One of the emerging and severely understudied subcortical targets of the PL cortex implicated in cocaine reward and relapse to cocaine seeking is the paraventricular nucleus of the thalamus (PVT). PL inputs to the PVT have been implicated in fear-induced anxiogenic behaviors as well as relapse to cocaine seeking. However, little is known about the contribution of PL-->PVT in cocaine withdrawal-induced anxiety. Therefore, in this study, we explored the implications of chemogenetically inhibiting PL-->PVT projections using a combinatorial AAV vector approach in the attenuation of cocaine-induced anxiogenic behaviors during early withdrawal from cocaine using an elevated zero maze (EZM) and an open field test (OFT). We hypothesized that cocaine withdrawal-induced anxiety-like behavior would be greater than that in saline control rats on the EZM and OFT tasks. Further, inhibition of the PL-->PVT projection would attenuate cocaine withdrawal-induced anxiogenic behaviors and therefore decrease the probability of subsequent relapse to cocaine seeking. Additionally, we predicted that PL-->PVT inhibition would not affect anxiety-like behavior in saline control rats. Results from our study demonstrate that PL-->pPVT inhibition decreased the latency to enter open arms but increased the number of explorations of the open arms in rats with cocaine experience compared to yoked-saline controls. In the same animals, inhibition of PL-->pPVT increased the time spent in the center of the open field in rats with cocaine experience. Together, our results demonstrate that the PL-->pPVT projection influences aspects of the anxiety phenotype associated with exploratory behaviors. Inhibition of the PLàPVT pathway during early withdrawal from cocaine attenuated withdrawal-induced anxiogenic behaviors and this inhibition did not affect baseline anxiety-like behaviors in control rats. Therefore, this study provides evidence for the involvement of the PL-->PVT pathway in mediating cocaine withdrawal-induced anxiety.

Rights

Copyright is held by the author. All rights reserved.

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