Prolonged-access to cocaine induces distinct Homer2 DNA methylation, hydroxymethylation, and transcriptional profiles in the dorsomedial prefrontal cortex of Male Sprague-Dawley rats.
Prolonged-access to cocaine induces distinct Homer2 DNA methylation, hydroxymethylation, and transcriptional profiles in the dorsomedial prefrontal cortex of Male Sprague-Dawley rats.
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DOI：
10.1016/j.neuropharm.2018.09.029
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发表时间：
2018-12
影响因子：
4.7
通讯作者：
Kippin TE
中科院分区：
文献类型：
--
作者：
Ploense KL;Li X;Baker-Andresen D;Carr AE;Woodward N;Bagley J;Szumlinski KK;Bredy TW;Kippin TE
重复服用可卡因会引起背侧内侧前额叶皮层 (dmPFC) 的许多长期结构和分子变化，并且已知这是可卡因寻求行为的基础。 DNA甲基化是基因表达的一个关键的长期表观遗传决定因素，并且与神经可塑性有关，然而，这种表观遗传修饰在与药物成瘾相关的神经可塑性中所涉及的程度受到的关注有限。在这里，我们检查了有限可卡因自我给药（1小时/天）、长期可卡因自我给药（6小时/天）和盐水自我给药（1小时/天）后背侧内侧前额叶皮质（dmPFC）内DNA甲基化和基因表达之间的关系。给大鼠安装静脉导管，并允许在不同的接入条件下杠杆按压生理盐水或可卡因（0.25 mg/kg/0.1 mL 输注），持续 20 天。长期接触的大鼠在训练过程中表现出可卡因摄入量的增加，而有限接触的大鼠则没有增加可卡因的摄入量。此外，有限访问和长期访问大鼠表现出独特的 Homer2 表观遗传特征和 mRNA 表达。在长时间接触的大鼠中，dmPFC 中的 Homer2 mRNA 水平增加，同时伴随着 Homer2 启动子内 DNA 甲基化和 p300 结合的减少。受限动物表现出 DNA 甲基化降低、DNA 羟甲基化降低以及 Homer2 启动子内 p300 结合增加。这些数据表明，不同的表观遗传特征是由有限的与长期的自我给药条件诱导的，这些条件有助于转录特征，并支持 DNA 的共价修饰与可卡因寻求行为的成瘾样变化有关的观点。
Repeated cocaine administration induces many long-term structural and molecular changes in the dorsal medial prefrontal cortex (dmPFC) and are known to underlie aspects of cocaine-seeking behavior. DNA methylation is a key long-lasting epigenetic determinant of gene expression and is implicated in neuroplasticity, however, the extent to which this epigenetic modification is involved in the neuroplasticity associated with drug addiction has received limited attention. Here, we examine the relation between DNA methylation and gene expression within the dorsal medial prefrontal cortex (dmPFC) following limited cocaine self-administration (1 h/day), prolonged cocaine self-administration (6 h/day), and saline self-administration (1 h/day). Rats were fitted with intravenous catheters and allowed to lever press for saline or cocaine (0.25 mg/kg/0.1 mL infusion) in the different access conditions for 20 days. Prolonged-access rats exhibited escalation in cocaine intake over the course of training, while limited-access rats did not escalate cocaine intake. Additionally, limited-access and prolonged-access rats exhibited unique Homer2 epigenetic profiles and mRNA expression. In prolonged-access rats, Homer2 mRNA levels in the dmPFC were increased, which was accompanied by decreased DNA methylation and p300 binding within the Homer2 promoter. Limited-access animals exhibited decreased DNA methylation, decreased DNA hydroxymethylation, and increased p300 binding within the Homer2 promoter. These data indicate that distinct epigenetic profiles are induced by limited-versus prolonged-access self-administration conditions that contribute to transcriptional profiles and lend support to the notion that covalent modification of DNA is implicated in addiction-like changes in cocaine-seeking behavior.
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影响因子：
3.4
作者：
Li X;Caprioli D;Marchant NJ
通讯作者：
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影响因子：
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作者：
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DOI：
10.1017/s1461145713000394
发表时间：
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影响因子：
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作者：
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通讯作者：
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作者：
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