| Cocaine abuse is a serious problem that threatens the U.S. today. Increased immediate early gene (IEG) expression by drugs of abuse has been implicated in the initial step by which these drugs alter the expression of late genes to produce long-lasting changes in neuronal function. An earlier microarray study identified the IEG fra-2 as being particularly sensitive to sigma receptor-mediated stimulant effects of cocaine. Therefore, in this study, we tested the hypothesis that the IEG fra-2 is critically involved in the transition between the immediate response to cocaine, and the more persistent changes that accompany repeated cocaine exposure. We also investigate whether the interaction between cocaine, sigma1 receptors, and fra-2 may explain the ability of sigma1 receptor antagonists to combat an array of behaviors following acute, as well as repeated, exposure to cocaine. The results from the studies reported herein showed that the prototypic sigma 1 receptor antagonist BD1063 can block cocaine-induced locomotor stimulant effects as well as behavioral sensitization. Gene and protein expression studies showed that fra-2 gene and protein expression was up-regulated when the animals received cocaine, suggesting that the up-regulation of fra-2 represents an early, immediate response to cocaine. In contrast, sigma1 receptor gene and protein expression showed progressive increases, which corresponded to the steady increase in the locomotor response to cocaine upon repeated exposures. This suggested that the progressive up-regulation of sigma 1 receptor gene and protein expression may contribute to the development of behavioral sensitization. Finally, a fra-2 antisense study showed that while fra-2 protein levels were significantly diminished by antisense treatment, sigma 1 receptor gene expression was up-regulated. However, when the animals were challenged with cocaine, fra-2 and sigma1 receptor gene expression was inhibited in the fra-2 antisense-treated groups in a dose-dependant manner. These results suggested that manipulation of fra-2 levels may be associated with the response of the sigma1 receptor gene to cocaine exposure. In summary, the results from this dissertation provide critical evidence from behavioral, gene, and protein expression studies to reveal new mechanisms that underlie the transition of the nervous system as it responds to acute vs. repeated cocaine exposure. |
