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

Abstract

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 (PARP-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 PARP-1 in cocaine-induced molecular, neural, and behavioral plasticity. Repeated cocaine administration, including self-administration, increased global levels of PARP-1 and its mark PAR in mouse nucleus accumbens (NAc), a key brain reward region. Using PARP-1 inhibitors and viral-mediated gene transfer, we established that PARP-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 PARP-1 in NAc of cocaine-exposed mice and identified several PARP-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 PARP-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 PARP-1 and PARylation in the long-term actions of cocaine.histone PARylation | drug addiction | medium spiny neurons

Epigenetic Signaling in Psychiatric Disorders

“…Chronic cocaine induces poly(ADP-ribose) polymerase-1 (PARP-1) in the NAc and this upregulation potentiates behavioral responses to cocaine. ChIP-seq revealed cocaine-induced increases in PARP-1 binding across the genome and this correlated with increased gene expression measured by RNA-seq 157 .…”

Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility

“…Neurod2 encodes a transcription factor that is important in neuronal differentiation and synapse maturation (Messmer et al, 2012; Olson et al, 2001; Wilke et al, 2012). Sdk1 is a cell-adhesion molecule that guides synapse formation in retina (Yamagata and Sanes, 2008; Yamagata et al, 2002), and recent work from our group has implicated Sdk1 in cocaine-induced spinogenesis in NAC (Scobie et al, 2014). Based on the pattern of DEGs with the MB and V modules (Figure 3C), we predicted that over-expressing the selected hub genes in VHIP vs. PFC would induce different effects on susceptibility to social defeat.…”

Histone arginine methylation in cocaine action in the nucleus accumbens

“…Genome-wide methods have increasingly been used to obtain an unbiased view of chromatin changes in animal models of psychiatric disorders including changes in the NAc in addiction models (4,9,11). In nonneural tissues, H3R2me2a has been shown to act as a repressive mark that antagonizes H3K4me3 (17,18).…”

“…Important aspects of cocaine action appear to be mediated by changes in gene transcription via chromatin regulatory mechanisms such as histone acetylation or methylation on Lys (K) residues (3)(4)(5)(6)(7)(8)(9)(10)(11). However, in contrast to K methylation, the functional role of histone Arg (R) methylation remains underexplored in addiction models and poorly understood in the brain in general.…”