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 (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.
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Kimberly N
KN
Scobie
Diane
D
Damez-Werno
HaoSheng
H
Sun
NingYi
N
Shao
Amy
A
Gancarz
Clarisse H
CH
Panganiban
Caroline
C
Dias
JaWook
J
Koo
Paola
P
Caiafa
Lewis
L
Kaufman
Rachael L
RL
Neve
David M
DM
Dietz
Li
L
Shen
Eric J
EJ
Nestler
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D016678:Genome / Q000235:genetics; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects / Q000201:enzymology; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013379:Substrate Specificity / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
D007074:Immunoglobulin G; D008565:Membrane Proteins; D012333:RNA, Messenger; C493090:sidekick-1 protein, mouse; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases; D003042:Cocaine
drug addiction; histone PARylation; medium spiny neurons