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
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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.
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