Date of Award

2018

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Jacqueline F. McGinty

Second Advisor

Peter W. Kalivas

Third Advisor

John J. Woodward

Fourth Advisor

William C. Griffin, III

Fifth Advisor

Paul J. Lombroso

Sixth Advisor

Joseph B. Blumer

Abstract

The primary goal of this dissertation is to further examine the role of the prelimbic (PrL) subdivision of the rodent medial prefrontal cortex in relapse to cocaine seeking following abstinence, and to extend our understanding of pathway-specific adaptations in the PrL cortex projection to the nucleus accumbens (NAc) core that drives relapse. Previous findings indicate that the PrL cortex shows a biphasic response to abstinence from cocaine exposure. Specifically, early withdrawal (two hours after the final self-administration session) results in dephosphorylation of glutamate NMDA receptors and glutamate signaling regulators including extracellular signal-regulated kinase and the downstream transcription factor cAMP response-element binding protein (CREB). One week of abstinence enhances p-CREB and AMPA receptor subunit GluA1 phosphorylation in the PrL cortex, and Synapsin I in the NAc core. Interventions that act to normalize glutamate transmission in the PrL cortex during early withdrawal provide an enduring suppression of drug-seeking by normalizing activity in the PrL-NAc core pathway. Using a combination of biochemical and behavioral pharmacology techniques, we have found that the cocaine-induced activation of STriatal-Enriched protein tyrosine Phosphatase in the PrL cortex during early withdrawal plays a role in subsequent cocaine seeking by dephosphorylating extra-cellular signal-regulated kinase. We also show that chemogenetic-mediated activation of the PrL cortex, or PrL-NAc core neurons, immediately after self-administration transiently reduces drug seeking which is not sustained. Finally, using an array of immunohistochemistry, pathway-specific viral vectors, and high-resolution confocal microscopy techniques, we provide evidence that PrL-NAc core neurons show reduced immunoreactivity of the activity markers Fos and p-CREB, reduced dendritic spine head diameter, and reduced GluA1/2 expression in subsets of dendritic spines during early withdrawal. The opposite effect was found after one week of abstinence. At this timepoint, PrL-NAc core neurons showed heightened nuclear p-CREB, spine head diameter, and GluA1/2 expression in dendritic spines. These findings suggest that the PrL cortex, and specifically PrL-NAc core neurons, undergoes an abstinence duration-dependent transformation in glutamate transmission which may be regulated by the activation of STEP during early withdrawal.

Rights

All rights reserved. Copyright is held by the author.

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