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The effects of chronic intermittent ethanol exposure on withdrawal related behaviors, dopamine terminal function and kappa opioid system sensitivity in the nucleus accumbens core

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abstract
Alcohol use disorders are a rampant economic and health concern in the United States. Chronic alcohol use and abstinence is often followed by relapse to ethanol drinking occurs in response to the withdrawal symptoms of the drug. However, the neurobiological underpinnings of this disorder are not well understood. Previous work has shown that chronic ethanol exposure and withdrawal downregulates dopamine transmission in the nucleus accumbens (NAc). Reduced dopamine terminal function may be due to upregulated presynaptic receptor proteins such as kappa opioid receptors (KOR) and dopamine D2/D3 autoreceptors (D2R/D3R), and changes in receptor-system function may, in part, drive symptoms of ethanol withdrawal and subsequent relapse drinking behavior. To this end, the present body of work identified some of the effects of five weeks of chronic intermittent ethanol (CIE) exposure on ethanol withdrawal behavioral phenotypes, including ethanol drinking parameters and anxiety/compulsive-like behavior, as well as dopamine transmission and presynaptic receptor function in the NAc of C57BL/6J mice. We found that CIE increased ethanol drinking and anxiety/compulsive-like marble burying compared to air-exposed mice, phenotypes that were reduced by KOR blockade and replicated with KOR activation. Neurobiological examination of accumbal dopamine transmission with fast scan cyclic voltammetry in brain slices showed reduced dopamine release, augmented uptake and increased sensitivity of KORs and D3Rs following five weeks of CIE exposure. A subsequent examination of interactions between KORs and dopamine autoreceptors showed that D3Rs and KORs are functionally linked. Finally, the effects nalmefene, a high-affinity KOR partial agonist used in some European countries to treat alcohol use disorders, on dopamine terminal and KOR function were examined in efforts to understand its clinical efficacy. Nalmefene reduced dopamine uptake rates and reversed the dopamine-decreasing effects of KOR activation selectively in brain slices from CIE-exposed mice. These effects are credited to the increased affinity and distinct effects of this compound on KORs. We hope that this work supports the development of KOR-specific lignads to reduce ethanol withdrawal symptoms and relapse drinking. A discussion of the present data, future directions, clinical implications of this work and experimental caveats are considered.
subject
behavior
c57bl
mouse
voltammetry
contributor
Rose, Jamie Hannah (author)
Jones, Sara R (committee chair)
Chen, Rong (committee member)
McCool, Brian A (committee member)
Milligan, Carolanne E (committee member)
Weiner, Jeffrey L (committee member)
date
2016-01-11T09:35:25Z (accessioned)
2016-07-10T08:30:12Z (available)
2015 (issued)
degree
Physiology and Pharmacology (discipline)
embargo
2016-07-10 (terms)
identifier
http://hdl.handle.net/10339/57439 (uri)
language
en (iso)
publisher
Wake Forest University
title
The effects of chronic intermittent ethanol exposure on withdrawal related behaviors, dopamine terminal function and kappa opioid system sensitivity in the nucleus accumbens core
type
Dissertation

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