Withdrawal from repeated morphine administration augments expression of the RhoA network in the nucleus accumbens to control synaptic structure.
Withdrawal from repeated morphine administration augments expression of the RhoA network in the nucleus accumbens to control synaptic structure.
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DOI：
10.1111/jnc.14563
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发表时间：
2018-10
影响因子：
4.7
通讯作者：
Nestler EJ
中科院分区：
文献类型：
--
作者：
Cahill ME;Browne CJ;Wang J;Hamilton PJ;Dong Y;Nestler EJ
伏隔核（NAc）是一个关键的大脑奖赏区域，它介导滥用药物（包括吗啡和其他阿片类药物）的奖赏效应。滥用药物会引起 NAc 中型多棘神经元 (MSN) 基因转录和树突棘形态的广泛改变，最终影响 NAc 兴奋性，从而影响与奖励相关的行为反应。越来越多的证据表明，NAc 中的小 GTP 酶是滥用药物的常见细胞内靶标，这些分子调节药物介导的转录和脊柱形态发生效应。 RhoA 小 GTP 酶是 Ras 小 GTP 酶超家族中最有特色的成员之一，最近的工作强调了海马 RhoA 在吗啡促进的奖赏行为中的重要作用。尽管如此，尚不清楚吗啡戒断如何影响 NAc 中的 RhoA 通路信号传导。为了研究这个问题，我们使用亚细胞分级分离和随后的蛋白质分析，检测了重复吗啡给药的多个停药期期间 NAc 核、细胞质和突触体区室中 RhoA 途径关键成分的表达。此外，利用体内病毒介导的基因转移，我们确定了 RhoA 通路改变对 NAc MSN 树突棘形态的影响。我们的研究结果揭示了 RhoA 信号级联在介导长期吗啡戒断对 NAc MSN 树突棘消除的影响中发挥着重要作用。在重复吗啡给药的多个停药期后，在来自伏核组织的细胞核、细胞质和突触体部分中检查了 RhoA 网络的表达谱。我们发现短期吗啡戒断会增加核部分中 RhoA 网络关键成分的表达，并且这种增加针对特定的肌动蛋白细胞骨架状态。另一方面，长期吗啡戒断会增加突触体部分中 RhoA 网络成分的表达。这些发现对于理解阿片戒断期间导致药物寻求行为的机制具有重要意义。
The nucleus accumbens (NAc) is a critical brain reward region that mediates the rewarding effects of drugs of abuse, including those of morphine and other opiates. Drugs of abuse induce widespread alterations in gene transcription and dendritic spine morphology in medium spiny neurons (MSNs) of the NAc that ultimately influence NAc excitability and hence reward-related behavioral responses. Growing evidence indicates that within the NAc small GTPases are common intracellular targets of drugs of abuse where these molecules regulate drug-mediated transcriptional and spine morphogenic effects. The RhoA small GTPase is among the most well-characterized members of the Ras superfamily of small GTPases, and recent work highlights an important role for hippocampal RhoA in morphine-facilitated reward behavior. Despite this, it is unclear how RhoA pathway signaling in the NAc is affected by withdrawal from morphine. To investigate this question, using subcellular fractionation and subsequent protein profiling we examined the expression of key components of the RhoA pathway in NAc nuclear, cytoplasmic, and synaptosomal compartments during multiple withdrawal periods from repeated morphine administration. Further, using in vivo viral-mediated gene transfer, we determined the consequences of revealed RhoA pathway alterations on NAc MSN dendritic spine morphology. Our findings reveal an important role for RhoA signaling cascades in mediating the effects of long-term morphine withdrawal on NAc MSN dendritic spine elimination. The expression profile of the RhoA network was examined in nuclear, cytosolic, and synaptosomal fractions from nucleus accumbens tissue following multiple withdrawal periods from repeated morphine administration. We found that short-term morphine withdrawal increases the expression of a key component of the RhoA network in nuclear fractions, and this increase is directed toward specific actin cytoskeleton states. Long-term morphine withdrawal, on the other hand, increases expression of a component of the RhoA network in synaptosomal fractions. These findings have implications for understanding the mechanisms that contribute to drug-seeking behavior during opiate withdrawal.
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DOI：
10.1038/nrm2890
发表时间：
2010-05
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1165/rcmb.2002-0206oc
发表时间：
2003-07-01
影响因子：
6.4
作者：
Liu, HW;Halayko, AJ;Solway, J
通讯作者：
Solway, J
影响因子：
3.7
作者：
Li N;McMurry T;Berg A;Wang Z;Berceli SA;Wu R
通讯作者：
Wu R
影响因子：
7.6
作者：
Fakira, Amanda K.;Massaly, Nicolas;Moron, Jose A.
通讯作者：
Moron, Jose A.
影响因子：
2.9
作者：
Penzes, Peter;Cahill, Michael E.
通讯作者：
Cahill, Michael E.