背侧纹状体组蛋白去乙酰化酶 5 在甲基苯丙胺成瘾潜伏期的作用。
Role of Dorsal Striatum Histone Deacetylase 5 in Incubation of Methamphetamine Craving.
机构信息
Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland.
Neuroscience Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas.
出版信息
Biol Psychiatry. 2018 Aug 1;84(3):213-222. doi: 10.1016/j.biopsych.2017.12.008. Epub 2017 Dec 29.
BACKGROUND
Methamphetamine (meth) seeking progressively increases after withdrawal (incubation of meth craving). We previously demonstrated an association between histone deacetylase 5 (HDAC5) gene expression in the rat dorsal striatum and incubation of meth craving. Here we used viral constructs to study the causal role of dorsal striatum HDAC5 in this incubation.
METHODS
In experiment 1 (overexpression), we injected an adeno-associated virus bilaterally into dorsal striatum to express either green fluorescent protein (control) or a mutant form of HDAC5, which strongly localized to the nucleus. After training rats to self-administer meth (10 days, 9 hours/day), we tested the rats for relapse to meth seeking on withdrawal days 2 and 30. In experiment 2 (knockdown), we injected an adeno-associated virus bilaterally into the dorsal striatum to express a short hairpin RNA either against luciferase (control) or against HDAC5. After training rats to self-administer meth, we tested the rats for relapse on withdrawal days 2 and 30. We also measured gene expression of other HDACs and potential HDAC5 downstream targets.
RESULTS
We found that HDAC5 overexpression in dorsal striatum increased meth seeking on withdrawal day 30 but not day 2. In contrast, HDAC5 knockdown in the dorsal striatum decreased meth seeking on withdrawal day 30 but not on day 2; this manipulation also altered other HDACs (Hdac1 and Hdac4) and potential HDAC5 targets (Gnb4 and Suv39h1).
CONCLUSIONS
Results demonstrate a novel role of dorsal striatum HDAC5 in incubation of meth craving. These findings also set up future work to identify HDAC5 targets that mediate this incubation.
背景
甲基苯丙胺（冰毒）在戒断后（觅药动机的潜伏期）逐渐增加。我们之前证明了大鼠背侧纹状体中的组蛋白去乙酰化酶 5（HDAC5）基因表达与觅药动机的潜伏期之间存在关联。在这里，我们使用病毒构建体来研究背侧纹状体 HDAC5 在这种潜伏期中的因果作用。
方法
在实验 1（过表达）中，我们将腺相关病毒双侧注射到背侧纹状体中，以表达绿色荧光蛋白（对照）或强定位到核的 HDAC5 突变体。在训练大鼠自我注射冰毒（10 天，每天 9 小时）后，我们在戒断日 2 和 30 测试大鼠对冰毒觅药的复发情况。在实验 2（敲低）中，我们将腺相关病毒双侧注射到背侧纹状体中，以表达针对荧光素酶（对照）或针对 HDAC5 的短发夹 RNA。在训练大鼠自我注射冰毒后，我们在戒断日 2 和 30 测试大鼠的复发情况。我们还测量了其他 HDACs 和潜在的 HDAC5 下游靶点的基因表达。
结果
我们发现，背侧纹状体中的 HDAC5 过表达增加了戒断日 30 时的冰毒觅药，但不会增加戒断日 2 时的冰毒觅药。相比之下，背侧纹状体中的 HDAC5 敲低降低了戒断日 30 时的冰毒觅药，但不会降低戒断日 2 时的冰毒觅药；这种操作还改变了其他 HDACs（Hdac1 和 Hdac4）和潜在的 HDAC5 靶点（Gnb4 和 Suv39h1）。
结论
这些结果证明了背侧纹状体 HDAC5 在冰毒觅药的潜伏期中具有新的作用。这些发现还为确定介导这种潜伏期的 HDAC5 靶点奠定了未来的工作基础。
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