A hallmark of addiction is excessive drug-seeking behavior which is believed to be mediated by pathological changes in a number of brain structures, including the prefrontal cortex, involving drug-induced alterations in gene expression. Chromatin remodeling or epigenetic regulation is a key determinant of gene expression that has recently been implicated in drug-induced neuroplasticity. The present project will develop a collaborative effort been the Principal Investigator (Kippin), whose expertise is in behavioral neuroscience, and the co-Principal Investigator (Sun), whose expertise is in epigenetics, to explore chromatin remodeling produced during a rat cocaine self-administration model of addiction. Specifically, this study is based on a rat model of cocaine self-administration (via a i.v. catheter) with either short or prolonged daily access with the latter condition leading to a time-dependent escalation of cocaine intake and subsequent relapse vulnerability which is similar to the pattern observed in cocaine addiction. Based on the results of a high-throughput, genome-wide analysis of DNA methylation using a MeDIP-CHIP assay in the dorsal medial prefrontal cortex produced by prolonged access to cocaine self- administration, the present application will verify methylation in genes of interest, determine the consequences for expression of those genes (at mRNA and protein levels), determine changes in the epigenetic machinery produced by cocaine exposure, and determine the enduring nature of these changes across 2 months of cocaine withdrawal. The long-term goals of this project are to establish the utility of high-throughput DNA methylation and other techniques to identify molecular targets involved in addiction as well as establish a collaboration between our laboratories to map changes in chromatin remodeling (both DNA methylation and histone modifications) in neural circuits mediating motivational and cognitive processes that are disrupted in addiction. These studies will provide a more detailed understanding of the role of chromatin remodeling to the brain pathology associated with the addiction process.
Changes in gene expression are widely implicated in the pathological function of brain structures during the addiction processes. The present project will determine the contribution of chromatin remodeling, specifically DNA methylation, to gene expression changes within the prefrontal cortex that are produced in a rat model of excessive cocaine intake. These experiments will establish a framework for studying the long-term changes in genetic function at the chromatin modification level in addiction through the employment of high-throughput molecular techniques combined with diseases relevant behavioral models in order to inform our understanding of addiction-related brain pathology.
