Date of Award

2017

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Patrick Mulholland

Second Advisor

John J. Woodward

Third Advisor

Howard C. Becker

Fourth Advisor

William C. Griffin

Fifth Advisor

Betsy M. Ferguson

Abstract

Stress is a critical component in the development, maintenance, and reinstatement of addictive behaviors, including alcohol addiction. Since anxiety and mood disorders frequently overlap with an AUD, it is important to determine the neural mechanisms associated with chronic exposure to alcohol and stress. It is known that chronic alcohol and stress exposure elicit neuroadaptive changes in brain regions that are critical in addiction- and stress-related pathways. Although the NAc is heavily implicated in goal-directed behavior and plays a critical role in the addiction-circuit, it has been suggested that the PFC appears to process the events that directly trigger relapse which include: exposure to acute stress, cues previously associated with the drug, and the drug itself. In addition, lesions or inactivation of the mPFC or NAc prevent reinstatement of drug-seeking following extinction, while activation of either structure stimulates drug-seeking behaviors. Pre-clinical and clinical evidence suggests the mPFC and NAc are vulnerable to alcohol- and stress-induced changes. Chronic alcohol exposure or prolonged alcohol self- administration significantly reduced KCa2 channel function or expression in the mPFC and NAc, and growing preclinical evidence suggests KCa2 channels may be promising therapeutic targets to treat alcohol- and stress-related comorbid disorders. Recent preclinical findings demonstrate that chronic stress exposure increases KCa2 channel expression and creates a depressive-like phenotype in rodent models. In addition, pharmacological manipulation or genetic depletion of KCa2 channels bi-directionally modulate alcohol consumption and alter coping behaviors during acute stress tests. Together, this work supports our overarching hypothesis that chronic stress and ethanol-exposure creates functional adaptations in the NAc and mPFC, which induce alcohol-dependent and anxiety-like behavioral phenotypes, and the modulation of KCa2 channels are potential therapeutic targets for treating alcohol- and stress-related comorbid disorders.

Rights

All rights reserved. Copyright is held by the author.

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