The clinical course of cocaine abuse has been characterized as progressing through a number of temporal stages that advance from initial experimentation through casual use and finally to addiction. On a neurobiological level, this clinical course is paralleled by changes in the response to cocaine with repeated exposure, as well as residual changes in brain function and structure that may persist despite prolonged periods of abstinence from drug use. The studies proposed in the present application will focus on the neuroadaptations that accompany long term exposure to cocaine. We will focus on animals self-administration models, as these models provide valid predictions of human cocaine abuse. Furthermore, differences in the behavioral, pharmacological, and neurochemical responses to cocaine have been shown between self- administered cocaine and cocaine administered non-contingently. In preliminary studies we have observed progressive changes in the patterns of functional activity with continued experience with cocaine self- administration. Structure that form part of the neuroanatomical circuit mediate cocaine self-administration in its initial stages are different from those that appear to be involved later in course of experience with self-administration. Such neuroadaptations may underlie the overall progression of self-administration as it eventually leads to addiction. The overall goals of this project, then are, (1) to extend these findings to examine more closely the evolution of the functional changes associated with cocaine self-administration; (2) to determine the temporal course of adaptations in dopamine and opioid systems that may underlie these changes in functional activity as they develop over time; and (3) to examine the long term effects of novel tropane analogs synthesized in this Center that have been hypothesized as potential medications for cocaine addiction. It is hoped that this approach will provide important insights into the progressive changes that accompany cocaine abuse and provide a basis for developing pharmacological therapies treatments for addiction.
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