Defense Date

2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Michael Miles

Abstract

Alcoholism is a persistent substance abuse disorder that is associated with negative health, social, and economic outcomes. Treatment strategies for alcohol use disorders are limited, and only three drugs have been approved by the FDA for treatment. Although behavioral therapy and drug combination strategies improve abstinence outcomes, the majority of those in treatment will not achieve long-term abstinence. Therefore, better treatment strategies are needed. While much progress has been made toward understanding the neurobiology of alcoholism, this knowledge has not been effectively translated into treatment strategies. Animal models of alcohol drinking have been crucial to this research effort, but until recently there have been few procedures that effectively model alcoholism by producing binge-like drinking, withdrawal, and relapse behavior. In the last five years the intermittent alcohol access (IAA) model, which uses repeated cycles of scheduled alcohol deprivation and reinstatement to elevate drinking, has been established as such a procedure, with substantial evidence that escalation of drinking produced by IAA is mediated by similar mechanisms as in human alcoholics, which include transcriptional regulation that alters functioning of mesolimbocortical reward pathways. The IAA model. The studies reported herein characterize changes in gene expression in mesolimbocortical brain regions associated with development of maladaptive binge-like alcohol drinking due to scheduled abstinence, particularly in the nucleus accumbens, which regulates motivated behavior. Furthermore the IAA model is characterized with regard to effectiveness in 2 ethanol-preferring C57BL/6 inbred mouse strains, and the influence of concurrent access to multiple alcohol concentrations is examined. Finally, the potential of naltrexone and novel mu-opioid receptor-selective antagonist NAQ to modulate alcohol drinking under continuous access and intermittent access procedures is reported. Microarray analysis is used to analyze the transcriptome in prefrontal cortex, nucleus accumbens, and ventral midbrain of C57BL/6NCrl mice after alcohol deprivation, and to identify differentially expressed genes and gene co-expression networks in C57BL/6J mice during continuous access, as well as after six cycles of IAA. Differentially expressed genes, network hub genes, and regulation mechanisms represent high priority targets for further study in binge-like drinking behavior, with the goal of translating this knowledge to treatment strategies for alcoholism.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

December 2013

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