Date of Award

2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Howard C. Becker

Second Advisor

Thomas C. Jhou

Third Advisor

Thomas L. Kash

Fourth Advisor

Patrick J. Mulholland

Fifth Advisor

John J. Woodward

Abstract

Alcohol Use Disorder (AUD) is a significant national and global public health problem. Of concern, binge drinking is the most common pattern of excessive alcohol consumption and serves as a risk factor for the development of AUD. Recent studies have implicated the dynorphin/kappa opioid receptor (DYN/KOR) neuropeptide system in this pattern of drinking but the precise circuitry mediating these effects are poorly understood. The central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) are two interconnected structures within the extended amygdala macrostructure that are rich in DYN/KOR and thought to contribute to binge drinking behavior. In the present studies, we demonstrate that KOR in the BNST contribute to excessive drinking by showing that site-specific delivery of a KOR antagonist decreased, while an agonist increased, binge-like alcohol consumption. Furthermore, we show that high levels of drinking induced by systemic administration of a KOR agonist were reversed by selective KOR blockade within the BNST. These findings suggest that KOR in the BNST promote binge drinking behavior, however, the endogenous dynorphinergic circuitry underlying this effect remains unknown. The CeA is a likely candidate in that it is involved in excessive drinking and sends dense dynorphinergic projections to the BNST (CeA-BNST-DYN+). In support of this hypothesis, we demonstrate that neuronal activity is increased within the CeA during a binge drinking session and that chemogenetic inhibition of the CeA-BNST-DYN+ pathway selectively decreased binge-like alcohol consumption. Collectively, these studies suggest that the CeA-BNST-DYN+ circuit contributes to binge-like alcohol consumption and KORs in the BNST likely mediate this effect. These studies provide valuable insight into neuronal circuitry underlying a key aspect of AUD and point to the DYN/KOR system as a potential therapeutic target for the treatment of excessive drinking.

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