Presynaptic mechanisms of ethanol : role of the microtubule and actin cytoskeleton in ethanol's inhibition of dopamine release : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
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[College Station, Tex.] :
[Texas A&M Health Science Center],
[2003]
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| Subjects: |
| Abstract: | ABSTRACT: Alcohol abuse is the third leading cause of premature death in the United States. However, the cellular mechanisms, primarily the presynaptic mechanisms, underlying addiction remain unclear. A central question in the complex field of alcohol addiction concerns identifying the proteins that are involved in alcohol reinforcement, tolerance, and relapse. Importantly, one characteristic of all drugs of abuse, including alcohol, is the release of dopamine in an area of the brain called the nucleus accumbens. Increases in dopamine in the nucleus accumbens appear to mediate the "rewarding" aspect of drug addition. Alcohol, like other addictive drugs, has been shown to stimulate dopamine release in the nucleus accumbens when administered acutely while chronic exposure can result in a "tolerance" to the acute effects. We have found that chronic ethanol exposure inhibits several forms of stimulated-dopamine release. Thus, we hypothesized that ethanol may alter general neurotransmitter release processes. The overall goal of the following study was to investigate the effects of chronic ethanol on specific neurotransmitter release proteins and cytoskeleton proteins involved in exocytosis. We investigated the role of the microtubule-transport system in ethanol's inhibition of neurotransmitter release. The results of these studies indicated that disruption of the microtubule-associated transport is unlikely to mediate ethanol's inhibition of neurotransmitter release. However, using several independent assays we found that chronic ethanol inhibits other important steps in neurotransmitter release. In order for neurotransmitter release to ensue under sustained stimulation, vesicles which are anchored in the presynaptic actin cytoskeleton must be released and moved from the reserve pool to the ready releasable pool near the nerve terminal membrane. We show that chronic ethanol appears to inhibit the refilling of the ready releasable pool of synaptic vesicles by inhibiting the breakdown of the presynaptic actin cytoskeleton upon stimulation. We further demonstrate that the mechanism of this inhibition of actin cytoskeleton breakdown may be an inhibition of the phosphorylation of proteins which are involved in the maintenance of the actin barrier. The presynaptic mechanisms of ethanol demonstrated here may potentially mediate adaptive responses such as tolerance and increase our understanding of the cellular and molecular basis of alcohol addiction. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 2003." Approved as to style and content by: Douglas P. Dohrman, James R. West, Wei-Jung A. Chen, Gerald D. Frye, James R. West (Head of Department). |
| Physical Description: | xi, 129 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 108-128). |