Persistent alterations in mesolimbic gene expression with abstinence from cocaine self-administration
Persistent alterations in mesolimbic gene expression with abstinence from cocaine self-administration
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DOI：
10.1038/sj.npp.1301577
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发表时间：
2008-07-01
影响因子：
7.6
通讯作者：
Vrana, Kent E.
中科院分区：
文献类型：
--
作者：
Freeman, Willard M.;Patel, Kruti M.;Vrana, Kent E.
在未戒断药物或短期戒断后，可卡因反应性基因表达变化已有描述。关于长期戒断后这些变化的持续性，数据很少。此前，我们报道在离散试验可卡因自我给药和10天强制戒断后，通过累进比率程序可观察到可卡因强化的潜伏效应。本研究利用大鼠离散试验可卡因自我给药和长期强制戒断来检测消退反应、已知可卡因反应性基因的mRNA丰度以及染色质重塑。在戒断30天和100天时，与戒断3天的大鼠相比，消退反应增强。观察到内侧前额叶皮质（mPFC）和伏隔核中c - fos、Nr4a1、Arc和EGRI mRNA均下降，并且在大多数情况下，这种下降在戒断100天内持续存在。信号肽CART和神经肽Y（NPY）在mPFC中短暂增加，但在戒断10天后恢复到基线水平。为了研究这些持续性mRNA变化的潜在调节机制，检测了mRNA表达改变的基因启动子处组蛋白H3乙酰化水平。在mPFC中，戒断1天和10天后，EGRI启动子处的组蛋白H3乙酰化降低。戒断1天后，NPY的H3乙酰化增加，在戒断10天后恢复到对照水平。从行为学上看，这些结果表明在离散试验可卡因自我给药和长期强制戒断后存在潜伏效应。这种潜伏效应伴随着基因表达的变化，这些变化在停止给药后很长时间内持续存在，并且可能受染色质重塑的调节。
Cocaine-responsive gene expression changes have been described after either no drug abstinence or short periods of abstinence. Little data exist on the persistence of these changes after long-term abstinence. Previously, we reported that after discrete-trial cocaine self-administration and 10 days of forced abstinence, incubation of cocaine reinforcement was observable by a progressive ratio schedule. The present study used rat discrete-trial cocaine self-administration and long-term forced abstinence to examine extinction responding, mRNA abundance of known cocaine-responsive genes, and chromatin remodeling. At 30 and 100 days of abstinence, extinction responding increased compared to 3-day abstinent rats. Decreases in both medial prefrontal cortex (mPFC) and nucleus accumbens c-fos, Nr4a1, Arc, and EGRI mRNA were observed, and in most cases persisted, for 100 days of abstinence. The signaling peptides CART and neuropeptide Y (NPY) transiently increased in the mPFC, but returned to baseline levels following 10 days of abstinence. To investigate a potential regulatory mechanism for these persistent mRNA changes, levels of histone H3 acetylation at promoters for genes with altered mRNA expression were examined. In the mPFC, histone H3 acetylation decreased after 1 and 10 days of abstinence at the promoter for EGRI. H3 acetylation increased for NPY after 1 day of abstinence and returned to control levels by 10 days of abstinence. Behaviorally, these results demonstrate incubation after discrete-trial cocaine self-administration and prolonged forced abstinence. This incubation is accompanied by changes in gene expression that persist long after cessation of drug administration and may be regulated by chromatin remodeling.