Essential role of poly(ADP-ribosyl)ation in cocaine action.

Many of the long-term effects of cocaine on the brain's reward circuitry have been shown to be mediated by alterations in gene expression. Several chromatin modifications, including histone acetylation and methylation, have been implicated in this regulation, but the effect of other histone modifications remains poorly understood. Poly(ADP-ribose) polymerase-1 a ubiquitous and abundant nuclear protein, catalyzes the synthesis of a negatively charged polymer called poly(ADP-ribose) or PAR on histones and other substrate proteins and forms transcriptional regulatory complexes with several other chromatin proteins. Here, we identify an essential role for in cocaine-induced molecular, neural, and behavioral plasticity. Repeated cocaine administration, including self-administration, increased global levels of Pduanyu37-1 and its mark PAR in mouse nucleus accumbens (NAc), a key brain reward region. Using Pduanyu37-1 inhibitors and viral-mediated gene transfer, we established that Pduanyu37-1 induction in NAc mediates enhanced behavioral responses to cocaine, including increased self-administration of the drug. Using chromatin immunoprecipitation sequencing, we demonstrated a global, genome-wide enrichment of Pduanyu37-1 in NAc of cocaine-exposed mice and identified several Pduanyu37-1 target genes that could contribute to the lasting effects of cocaine. Specifically, we identified sidekick-1--important for synaptic connections during development--as a critical Pduanyu37-1 target gene involved in cocaine's behavioral effects as well as in its ability to induce dendritic spines on NAc neurons. These findings establish the involvement of Pduanyu37-1 and PARylation in the long-term actions of cocaine.

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