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Functional Neurogenomics of Cocaine

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Functional Neurogenomics of Cocaine
Freeman, Willard Morgan
Dissertation prepared under the direction of Kent E. Vrana, Ph.D., Associate Professor of Physiology and Pharmacology and Director of Graduate Studies Chronic cocaine abuse causes altered neuronal gene expression, morphology, and physiology. These changes are thought to contribute to an allostatic state of behavior characterized by compulsive drug seeking, sensitization, tolerance, withdrawal and psychological dependence. Through the use of cDNA hybridization arrays and immunoreactive protein quantification, gene expression analysis can be carried out on a functional neurogenomic scale. This dissertation research identifies changes in gene expression across three animal models of chronic cocaine administration (non-contigent non-human primate, non-contingent rat, and self-administering rat), and three brain regions, (nucleus accumbens, frontal cortex, and hippocampus). In the non-human primate, chronic cocaine induced the expression of protein tyrosine kinase 2, mitogen activated protein kinase kinase, â-catenin, and protein kinase A á catalytic subunit. While each of these genes has important cellular effects, the prime finding of the study was that they all serve to activate cyclic AMP response element binding protein or activator protein 1, known mediators of cocaine-responsive gene expression x and behavior. In the non-contingent rodent model, hippocampal expression of protein kinase Cá, protein kinase Cå, metabotropic glutamate receptor 5, potassium channel Kv1.1, protein tyrosine kinase 2, and â-catenin were induced by cocaine. Each of these genes could potentially have a number of effects, but, interestingly, some of the changes observed could act in an antagonistic manner. In the rat frontal cortex, induction of protein tyrosine kinase 2, activity-regulated cytoskeletal protein, and a nuclear receptor 77 related antigen were seen with chronic cocaine administration. In the rat nucleus accumbens, protein tyrosine kinase 2 protein was shown to be significantly up-regulated. Initial hybridization array analysis of cocaine self-administering rats has produced a number of potentially cocaineresponsive genes, some of which were observed in the non-contingent rat model. These studies demonstrate that some changes in gene expression are specific to certain regions of the brain and others are more ubiquitous. These changes in gene expression provide hypotheses for future research into the role of functional neurogenomics in physiology and behavior, and may provide potential targets for pharmacotherapeutic intervention.
mitcheet@wfu.edu (authorEmail)
Doanld W. Bowden, Ph.D. (committee chair)
David C.S. Roberts, Ph.D. (committee member)
Sara R. Jones, Ph.D. (committee member)
Michael A. Nader, Ph.D. (committee member)
Kent E. Vrana, Ph.D. (committee member)
Freeman, Willard Morgan
2008-09-28T10:55:24Z (accessioned)
2010-06-18T18:57:08Z (accessioned)
2003-03-28 (available)
2008-09-28T10:55:24Z (available)
2010-06-18T18:57:08Z (available)
2002 (issued)
null (defenseDate)
Pharmacology (discipline)
Wake Forest University (grantor)
PHD (level)
http://hdl.handle.net/10339/14669 (uri)
etd-03282002-103535 (oldETDId)
Release the entire work immediately for access worldwide. (accessRights)
I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Wake Forest University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. (license)

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