Date of Award

2015

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Patrick J. Mulholland

Second Advisor

Howard C. Becker

Third Advisor

L. Judson Chandler

Fourth Advisor

William C. Griffin, III

Fifth Advisor

Antonieta Lavin

Sixth Advisor

Arthur C. Riegel

Abstract

Alcohol use disorder (AUD) is a major public health issue that produces enormous societal and economic burdens. Current FDA-approved pharmacotherapies for treating AUD suffer from deleterious side effects and are only effective in a subset of individuals, representing a need for improved medications for the management of AUD. The experiments described in this dissertation provide evidence for a complex relationship between Kv7 channels and alcohol-related behaviors that spans genetics, behavioral pharmacology, and biochemical adaptations suggesting these channels are a target for treating AUD. We first examined the genetic relationship between Kcnq genes and alcohol-related behaviors, showing that these channels contribute to an alcohol drinking phenotype. Behavioral pharmacology studies strengthened this relationship by showing that systemic administration and microinjections of retigabine, an FDA-approved anticonvulsant and Kv7 channel positive modulator, to components of the addiction neurocircuitry reduced voluntary consumption in a long-term intermittent access model in an alcohol-specific manner. Finally, we investigated alcohol-induced neuroadaptations in the nucleus accumbens (NAc). Specifically, we observed that long-term drinking enhanced sensitivity to the pro-convulsant effects of Kv7 channel blockade, altered surface trafficking of Kv7.2 channels between detergent resistant and soluble membranes, and reduced Kv7.2 channel SUMOylation in the NAc. To our knowledge, these data are the first to show evidence for post-translation modification by SUMOylation in a model of alcohol or drug exposure. Altogether the work presented in this dissertation indicates that retigabine may be a promising treatment for AUD, and that Kv7 channels are a target of alcohol-induced neuroadaptations.

Rights

All rights reserved. Copyright is held by the author.

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