Drug addiction has many components ranging from the immediate rewarding effects of the drug, escalation of drug intake, compulsive drug seeking and a tendency to relapse even many years after withdrawal, which can be the most difficult component to address from a clinical perspective. At its heart the changes in the addict's brain represent a long-lasting neuronal adaptation that must have an underlying cellular and molecular component. This has led some researchers to propose that mechanisms similar to those that mediate normal learning in memory are also involved in addiction. It has been known for many years that the consolidation of long-lasting memories requires new gene expression. This is a particularly attractive mechanism for mediating very long-lasting changes in neuronal function and work with transcription factors such as CREB and fos have supported the notion that addiction and normal memory may have common underlying molecular mechanisms. Transcriptional regulation is a complex process that requires not only the recruitment of transcription factors to the DNA but also specific modifications of chromatin structure. These epigenetic modifications are of critical importance and we have recently demonstrated using a mutant mouse that the histone acetyltransferase function of the transcriptional coactivator CBP is necessary for the development of normal long-term memory. Moreover, we showed that these behavioral deficits could be overcome using a histone deacetylase inhibitor currently in preliminary clinical trials. Since CBP is a major coactivator for CREB based transcription, which has been implicated in various addiction models, we postulate that CBP histone acetyltransferase function may be critical for long-lasting neuronal modulation in these paradigms as well. We will therefore examine behavioral sensitization of the psychomotor activating effects of cocaine, a nonassociative process, and the context-specificity of cocaine sensitization, an associative process in the CBP mutant mice. If deficits are obtained we will test the ability of histone deacetylase inhibitors to rescue these phenotypes. In this way we hope to expand our understanding of the transcriptional control of addictive mechanisms and identify new targets for potential therapeutic intervention. ? ? ?
