title: Drug experience epigenetically primes Fosb gene inducibility in rat nucleus accumbens.
abstract: ΔFosB, a Fosb gene product, is induced in nucleus accumbens (NAc) and caudate-putamen (CPu) by repeated exposure to drugs of abuse such as cocaine. This induction contributes to aberrant patterns of gene expression and behavioral abnormalities seen with repeated drug exposure. Here, we assessed whether a remote history of cocaine exposure in rats might alter inducibility of the Fosb gene elicited by subsequent drug exposure. We show that prior chronic cocaine administration, followed by extended withdrawal, increases inducibility of Fosb in NAc, as evidenced by greater acute induction of ΔFosB mRNA and faster accumulation of ΔFosB protein after repeated cocaine reexposure. No such primed Fosb induction was observed in CPu; in fact, subsequent acute induction of ΔFosB mRNA was suppressed in CPu. These abnormal patterns of Fosb expression are associated with chromatin modifications at the Fosb gene promoter. Prior chronic cocaine administration induces a long-lasting increase in RNA polymerase II (Pol II) binding at the Fosb promoter in NAc only, suggesting that Pol II "stalling" primes Fosb for induction in this region upon reexposure to cocaine. A cocaine challenge then triggers the release of Pol II from the gene promoter, allowing for more rapid Fosb transcription. A cocaine challenge also decreases repressive histone modifications at the Fosb promoter in NAc, but increases such repressive marks and decreases activating marks in CPu. These results provide new insight into the chromatin dynamics at the Fosb promoter and reveal a novel mechanism for primed Fosb induction in NAc upon reexposure to cocaine.
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors: Diane
authors: D
authors: Damez-Werno
authors: Quincey
authors: Q
authors: LaPlant
authors: HaoSheng
authors: H
authors: Sun
authors: Kimberly N
authors: KN
authors: Scobie
authors: David M
authors: DM
authors: Dietz
authors: Ian M
authors: IM
authors: Walker
authors: Ja Wook
authors: JW
authors: Koo
authors: Vincent F
authors: VF
authors: Vialou
authors: Ezekiell
authors: E
authors: Mouzon
authors: Scott J
authors: SJ
authors: Russo
authors: Eric J
authors: EJ
authors: Nestler
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018765:Dopamine Uptake Inhibitors; C483820:Fosb protein, rat; D016760:Proto-Oncogene Proteins c-fos; D003042:Cocaine