Document Type

Dissertation - University Access Only

Award Date

2012

Degree Name

Doctor of Philosophy (PhD)

Department / School

Pharmaceutical Sciences

First Advisor

Shafiqur Rahman

Abstract

Brain nicotinic acetylcholine receptors (nAChRs) in the midbrain dopamine system were previously shown to regulate various addictive disorders, including nicotine addiction. Alcohol and nicotine are most frequently co-abused drugs. Given the strong correlation between nicotine and alcohol (ethanol) addiction, we hypothesized that nAChRs are critically involved in acute and chronic effects of ethanol and associated drinking behaviors; and regulate the cellular and molecular mechanisms underlying ethanol addiction. Therefore, the primary aim of this study was to investigate the role of nAChRs in regulating behavioral, cellular and molecular mechanisms implicated in the acute and chronic effects of ethanol using validated mouse models. First, we have examined the role of nAChRs in drinking-in-the-dark or free choice ethanol intake mimicking binge-like or preferential drinking in humans using nAChR partial agonists and antagonists. We have shown that reduction or blockade of nAChR activity decreases excess binge-like ethanol drinking and preference without affecting the natural reward. Second, we have elucidated and characterized the involvement of nAChRs and possible subtypes in regulating nicotine-induced increased ethanol consumption that are crucial for nicotine and ethanol co-abuse. Third, we have examined the nAChR mediated mechanisms in ethanol relapse following deprivation in ethanol dependent mice. We have demonstrated that modulation of nAChR function by partial agonists suppressed ethanol deprivation following multiple deprivations from chronic ethanol drinking effect, a model for ethanol relapse. In addition, we have determined the involvement of nAChRs in regulating the acute ethanol-induced increased dopamine function and metabolism in ventral striatum. Lastly, we have demonstrated that nAChR partial agonists reduce chronic ethanol drinkinginduced up-regulation of striatal 􀁓FosB, a stable transcription factor, thus suggesting the role of nAChRs in modulating long-term neuroadaptations. Taken together, data from these behavioral, neurochemical, and molecular studies provide strong evidence that nAChRs in the mid brain dopamine system regulate molecular pathways involved in acute and chronic effects of ethanol associated with ethanol drinking behaviors. Therefore, these studies support the hypothesis that brain nAChRs are important therapeutic targets for ethanol addiction.

Library of Congress Subject Headings

Ethanol -- Physiological effect
Nicotinic recceptors
Acetylcholine -- Receptors
Mice as laboratory animals

Publisher

South Dakota State University

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Rights Statement

In Copyright