Another important result from these first genome-wide studies of histone acetylation in cocaine responses is the new set of gene targets and signaling pathways revealed. In addition to identifying several genes previously implicated in cocaine responses (e.g. the genes for CDK5 [Cyclin-dependent kinase 5], AGS3 [Activator of G-protein signaling 3], PER2 [Period 2], DYN [Dynorphin], etc.), a new class of histone deacetylases, the sirtuins, was also found to be regulated by cocaine in the NAc [67]. Both sirt1 and sirt2 are hyperacetylated at histone H3 and have higher levels of mRNA in response to chronic cocaine exposure. ΔFosB appears to contribute to these transcriptional changes. Moreover, pharmacological manipulation of these enzymes potently regulates cocaine reward, illustrating how genome-wide ChIP-chip analyses can ultimately reveal novel gene targets involved in behavioral responses to drugs of abuse.
