TY - JOUR
T1 - Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum
AU - Kumar, Arvind
AU - Choi, Kwang Ho
AU - Renthal, William
AU - Tsankova, Nadia M.
AU - Theobald, David E H
AU - Truong, Hoang Trang
AU - Russo, Scott J.
AU - LaPlant, Quincey
AU - Sasaki, Teresa S.
AU - Whistler, Kimberly N.
AU - Neve, Rachael L.
AU - Self, David W.
AU - Nestler, Eric J.
N1 - Funding Information:
We would like to thank Dr. Devanjan Sikder (UT Southwestern), for technical advice and a critical reading of the manuscript, and Dr. Eric Olson (UT Southwestern), for providing HDAC4 cDNA. This work was supported by grants from the NIDA and NIMH.
PY - 2005/10/20
Y1 - 2005/10/20
N2 - Given that cocaine induces neuroadaptations through regulation of gene expression, we investigated whether chromatin remodeling at specific gene promoters may be a key mechanism. We show that cocaine induces specific histone modifications at different gene promoters in striatum, a major neural substrate for cocaine's behavioral effects. At the cFos promoter, H4 hyperacetylation is seen within 30 min of a single cocaine injection, whereas no histone modifications were seen with chronic cocaine, consistent with cocaine's ability to induce cFos acutely, but not chronically. In contrast, at the BDNF and Cdk5 promoters, genes that are induced by chronic, but not acute, cocaine, H3 hyperacetylation was observed with chronic cocaine only. ΔFosB, a cocaine-induced transcription factor, appears to mediate this regulation of the Cdk5 gene. Furthermore, modulating histone deacetylase activity alters locomotor and rewarding responses to cocaine. Thus, chromatin remodeling is an important regulatory mechanism underlying cocaine-induced neural and behavioral plasticity.
AB - Given that cocaine induces neuroadaptations through regulation of gene expression, we investigated whether chromatin remodeling at specific gene promoters may be a key mechanism. We show that cocaine induces specific histone modifications at different gene promoters in striatum, a major neural substrate for cocaine's behavioral effects. At the cFos promoter, H4 hyperacetylation is seen within 30 min of a single cocaine injection, whereas no histone modifications were seen with chronic cocaine, consistent with cocaine's ability to induce cFos acutely, but not chronically. In contrast, at the BDNF and Cdk5 promoters, genes that are induced by chronic, but not acute, cocaine, H3 hyperacetylation was observed with chronic cocaine only. ΔFosB, a cocaine-induced transcription factor, appears to mediate this regulation of the Cdk5 gene. Furthermore, modulating histone deacetylase activity alters locomotor and rewarding responses to cocaine. Thus, chromatin remodeling is an important regulatory mechanism underlying cocaine-induced neural and behavioral plasticity.
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U2 - 10.1016/j.neuron.2005.09.023
DO - 10.1016/j.neuron.2005.09.023
M3 - Article
C2 - 16242410
AN - SCOPUS:26944474790
SN - 0896-6273
VL - 48
SP - 303
EP - 314
JO - Neuron
JF - Neuron
IS - 2
ER -