September 2013

Document Type


Degree Name



Dept. of Behavioral Neuroscience


Oregon Health & Science University


Alcoholism is a disorder characterized by long-term, excessive intake of ethanol (EtOH). Chronic EtOH abuse is maintained by cycles of abstinence and relapse, and stress can induce relapse in dependent alcoholics. Even in non-dependent populations, evidence supports a key role for neural stress networks in high EtOH intake. Research on the neurobiology of stress and EtOH drinking will give insight into future strategies for managing psychiatric disease states. The aim of this dissertation was to identify the mechanisms by which a particular neural stress locus (the centrally projecting Edinger- Westphal nucleus; EWcp) contributes to excessive EtOH intake. Animal models are required for precise control over genetic and environmental variables that impact behavior, and C57BL/6J (B6) mice are widely-used due to their innate preference for EtOH-containing fluids. EtOH dependence can be modeled using forced vapor or diet EtOH exposure, but these methods are metabolic and psychological stressors capable of impacting neural systems in unexpected ways. Therefore, I implemented several free-choice EtOH drinking models in B6 mice. In some cases, mice voluntarily surpassed the National Institutes of Health criterion for “binge drinking” (blood EtOH concentrations >80 milligrams/deciliter). In Chapter 1, I characterized the genetic profile of the EWcp and compared it between two inbred mouse strains that serve as models for genetic differences in EtOHrelated traits. I identified several EWcp-enriched genes that were upregulated in high oral EtOH-drinking B6 mice relative to low oral EtOH-drinking DBA/2J mice, hinting that these genes could regulate EtOH-related behavior via the EWcp. In Chapter 2, an electrolytic lesion technique was combined with a genetic knockout approach to determine if a particular stress-related neuropeptide within the EWcp, urocortin-1 (Ucn1), was critical for EtOH consumption. EWcp lesion decreased EtOH preference in a Ucn1-dependent manner, providing the first functional evidence for EWcp-Ucn1 involvement in EtOH drinking. Further, Chapter 2 showed that genetic deletion of Ucn1 or its receptor (the corticotropin-releasing factor type-2 receptor) attenuated EtOH’s conditioned rewarding effects, but deletion of Ucn1 did not alter EtOH’s conditioned aversive effects. By altering several variables across multiple studies in genetic mutant mice, Chapter 3 showed that deletion of Ucn1 decreased EtOH drinking only when experiments lasted longer than four days, and when mice were offered escalating concentrations of EtOH. Chapter 3 also showed that deletion of the Ucn1 gene did not alter caloric intake, tastant drinking, EtOH sedation and tolerance, nor anxiety-like behavior. Chapter 4 compared the EWcp gene expression profile between EtOHexperienced and naïve mice, identifying genes that were altered either immediately following an EtOH drinking session, or after 24 hours of forced abstinence from EtOH. Genes encoding Ucn1 and other neuropeptide system components were upregulated in EtOH-experienced mice, relative to controls. Chapter 5 implemented EWcp-specific reduction of Ucn1 levels by viral-mediated gene interference, finding that EWcp-Ucn1 knockdown decreased anxiety-like behavior and long-term EtOH consumption without altering baseline consummatory behavior. Together, these experiments demonstrated that EWcp-Ucn1 drives voluntary EtOH consumption and related behaviors. Knowledge gained from this research may inform future treatment strategies for neurobiological disorders of stress and addiction.




School of Medicine



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