HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner
HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner
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DOI：
10.1073/pnas.1213364110
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发表时间：
2013-02-12
影响因子：
11.1
通讯作者：
Wood, Marcelo A.
中科院分区：
文献类型：
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作者：
Malvaez, Melissa;McQuown, Susan C.;Wood, Marcelo A.
非特异性组蛋白脱乙酰酶 (HDAC) 抑制已被证明可以以难以恢复的方式促进寻药行为的消失。一个关键的悬而未决的问题是哪种特定的 HDAC 参与了药物寻求行为的消失。使用选择性 HDAC3 抑制剂 RGFP966，我们研究了 HDAC3 在灭绝中的作用，并发现 RGFP966 的全身治疗以难以恢复的方式促进了小鼠的灭绝。我们还研究了促进消退是否与消退学习过程中消退巩固的增强有关，或者与表现或再巩固的负面影响有关。这些是用于调节灭绝的任何化合物的关键区别，因为特定行为的更快减少被解释为促进灭绝。通过行为范式的创新组合，我们发现 RGFP966 的单一治疗可以增强先前建立的可卡因条件位置偏好的消除，同时增强受试者体内的长期物体位置记忆。在消退巩固过程中，HDAC3 抑制促进了与边缘下皮层、海马体和伏核内基因表达相关的组蛋白乙酰化的独特模式。因此，寻求药物的消失不能用对表现的不利影响来解释。这些结果表明，HDAC3 抑制增强了与寻药行为消失相关的记忆过程。
Nonspecific histone deacetylase (HDAC) inhibition has been shown to facilitate the extinction of drug-seeking behavior in a manner resistant to reinstatement. A key open question is which specific HDAC is involved in the extinction of drug-seeking behavior. Using the selective HDAC3 inhibitor RGFP966, we investigated the role of HDAC3 in extinction and found that systemic treatment with RGFP966 facilitates extinction in mice in a manner resistant to reinstatement. We also investigated whether the facilitated extinction is related to the enhancement of extinction consolidation during extinction learning or to negative effects on performance or reconsolidation. These are key distinctions with regard to any compound being used to modulate extinction, because a more rapid decrease in a defined behavior is interpreted as facilitated extinction. Using an innovative combination of behavioral paradigms, we found that a single treatment of RGFP966 enhances extinction of a previously established cocaine-conditioned place preference, while simultaneously enhancing long-term object-location memory within subjects. During extinction consolidation, HDAC3 inhibition promotes a distinct pattern of histone acetylation linked to gene expression within the infralimbic cortex, hippocampus, and nucleus accumbens. Thus, the facilitated extinction of drug-seeking cannot be explained by adverse effects on performance. These results demonstrate that HDAC3 inhibition enhances the memory processes involved in extinction of drug-seeking behavior.