Changes in histone acetylation in the prefrontal cortex of ethanol-exposed adolescent rats are associated with ethanol-induced place conditioning
Changes in histone acetylation in the prefrontal cortex of ethanol-exposed adolescent rats are associated with ethanol-induced place conditioning
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DOI：
10.1016/j.neuropharm.2012.01.011
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发表时间：
2012-06-01
影响因子：
4.7
通讯作者：
Guerri, Consuelo
中科院分区：
文献类型：
--
作者：
Pascual, Maria;Do Couto, Bruno R.;Guerri, Consuelo
青春期饮酒会对饮酒动机产生长期影响。奖赏相关过程中的异常可塑性可能是青少年易受毒瘾影响的原因之一。我们已经证明，在青春期的大鼠中，狂欢般的乙醇治疗会导致多巴胺能系统的变化，并导致大脑奖赏区组蛋白的修饰。考虑到组蛋白乙酰化调节转录活性并导致药物诱导的基因表达和行为改变，我们提出了这样的假设，即乙醇能够通过修改青少年大脑奖励区域特定基因启动子中的组蛋白来诱导转录变化，以及这些事件是否与位置条件反射的获得有关。在给幼年和成年大鼠间断给予乙醇后，我们发现乙醇处理上调了青春期前额皮质组蛋白乙酰转移酶(HAT)的活性，并增加了CFos、CDK5和FosB启动子区域的组蛋白(H3或H4)乙酰化和H3(K4)甲基化。在注射乙醇前用丁酸钠抑制组蛋白脱乙酰基酶可增强HAT活性的上调和CFos、CDK5和FosB的组蛋白乙酰化。此外，在乙醇处理的青少年中，丁酸钠和乙醇联合应用延长了条件性位置厌恶的消退，并增加了乙醇的恢复效果，但在乙醇处理的成年大鼠中却没有。这些结果表明，青春期酒精暴露诱导染色质重塑，改变组蛋白乙酰化和甲基化，并改变乙醇对位置条件反射的影响。他们还表明，表观遗传机制可能会为青春期酗酒导致的药物成瘾开辟新的治疗途径。(C)2012爱思唯尔有限公司。保留所有权利。
Alcohol drinking during adolescence can induce long-lasting effects on the motivation to consume alcohol. Abnormal plasticity in reward-related processes might contribute to the vulnerability of adolescents to drug addiction. We have shown that binge-like ethanol treatment in adolescent rats induces alterations in the dopaminergic system and causes histone modifications in brain reward regions. Considering that histone acetylation regulates transcriptional activity and contributes to drug-induced alterations in gene expression and behavior, we addressed the hypothesis that ethanol is capable of inducing transcriptional changes by histone modifications in specific gene promoters in adolescent brain reward regions, and whether these events are associated with acquisition of place conditioning. After treating juvenile and adult rats with intermittent ethanol administration, we found that ethanol treatment upregulates histone acetyl transferase (HAT) activity in adolescent prefrontal cortex and increases histone (H3 or H4) acetylation and H3(K4) dimethylation in the promoter region of cFos, Cdk5 and FosB. Inhibition of histone deacetylase by sodium butyrate before ethanol injection enhances both up-regulation of HAT activity and histone acetylation of cFos, Cdk5 and FosB. Furthermore, co-administration of sodium butyrate with ethanol prolongs the extinction of conditioned place aversion and increased the reinstatement effects of ethanol in ethanol-treated adolescents, but not in ethanol-treated adult rats. These results indicate that ethanol exposure during adolescence induces chromatin remodeling, changes histone acetylation and methylation, and modify the effects of ethanol on place conditioning. They also suggest that epigenetic mechanisms might open up avenues to new treatments for binge drinking-induced drug addiction during adolescence. (C) 2012 Elsevier Ltd. All rights reserved.