UC Santa Barbara

The majority of addiction research examining the brain has centered on neuronal adaptations both resulting from cocaine use and contributing to the development of addiction. However, neurons constitute a small minority of the total cells within the central nervous system (CNS) and the role of glial cell types, which make up the vast majority of CNS cells, in cocaine addiction is largely unexplored. Imaging studies have revealed white matter deficits within the corpus callosum and post-mortem tissue analysis has revealed decreased oligodendrocyte-specific protein expression within the brains of chronic cocaine users. The extended access (6h/day) cocaine self-administration paradigm conducted in rodents is used to model the escalation of cocaine intake seen within human cocaine users and is critical for gaining insight to the molecular adaptations that result from excessive cocaine use. The series of experiments detailed in this dissertation utilize this model to address three specific aims: (1) characterize changes in glial-specific proteins and mRNA expression in cortical and limbic brain regions of rats with a history of extended access cocaine self-administration, (2) characterize the behavioral consequences of decreased myelin basic protein on a variety of prefrontal cortex-dependent tasks that are impaired following a history of cocaine use, and (3) to determine the functional significance of decreased myelin basic protein expression on behavioral measures in an animal model of cocaine addiction, including the acquisition and maintenance of intravenous cocaine, dose sensitivity, as well as the extinction and reinstatement of drug-seeking. Taken together, the experiments detailed herein provide further support for an enduring effect of cocaine on the expression of glial-specific proteins within the forebrain and highlight a role for myelin basic protein within the ventromedial prefrontal cortex in regulating impulsive choice, but not other cocaine addiction- related behaviors.