Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model
Genetic background and epigenetic modifications in the core of the nucleus accumbens predict addiction-like behavior in a rat model
复制标题
DOI：
10.1073/pnas.1520491113
复制
发表时间：
2016-05-17
影响因子：
11.1
通讯作者：
Akil, Huda
中科院分区：
文献类型：
--
作者：
Flagel, Shelly B.;Chaudhury, Sraboni;Akil, Huda
这项研究在大鼠身上提供了一个明显的遗传差异，在长期服用可卡因后，与成瘾相关的行为倾向存在明显的遗传差异。它依赖于选择性培育的高反应性(BHR)和低反应性(BLR)大鼠品系的使用，这些品系与“气质”相关的几个特征不同，包括新奇诱导的运动和冲动。我们发现，BHR大鼠表现出类似于人类成瘾的行为，包括持续的可卡因寻找和增加的可卡因寻找的恢复。为了揭示这种差异易损性的潜在潜在机制，我们专注于伏隔核的核心，并研究了先前与BHR/BLR差异有关的两个转录本的表达和表观遗传调节：成纤维细胞生长因子(FGF2)和多巴胺D2受体(D2)。与bHRs相比，bLRs的FGF2mRNA水平较低，FGF2启动子上组蛋白(H3K9me3)上抑制标记的关联性增加。这些差异在基础条件下很明显，甚至在长期服用可卡因后仍然存在。相比之下，BHRS在基础条件下有较低的D2mRNA，与D2启动子上的H3K9me3有更大的关联，随着自身给予可卡因的时间延长，这些差异不再明显。相关分析表明，D2时H3K9me3的关联可能是导致复发倾向的关键底物。这些发现表明，伏隔核核心的D2mRNA水平低，可能是通过表观遗传修饰介导的，可能会使个人更容易对可卡因上瘾。相比之下，低水平的FGF2可能是一个保护因素，即使在长期接触可卡因后，FGF2似乎也是不变的。
This study provides a demonstration in the rat of a clear genetic difference in the propensity for addiction-related behaviors following prolonged cocaine self-administration. It relies on the use of selectively bred high-responder (bHR) and low-responder (bLR) rat lines that differ in several characteristics associated with "temperament," including novelty-induced locomotion and impulsivity. We show that bHR rats exhibit behaviors reminiscent of human addiction, including persistent cocaine-seeking and increased reinstatement of cocaine seeking. To uncover potential underlying mechanisms of this differential vulnerability, we focused on the core of the nucleus accumbens and examined expression and epigenetic regulation of two transcripts previously implicated in bHR/bLR differences: fibroblast growth factor (FGF2) and the dopamine D2 receptor (D2). Relative to bHRs, bLRs had lower FGF2 mRNA levels and increased association of a repressive mark on histones (H3K9me3) at the FGF2 promoter. These differences were apparent under basal conditions and persisted even following prolonged cocaine self-administration. In contrast, bHRs had lower D2 mRNA under basal conditions, with greater association of H3K9me3 at the D2 promoter and these differences were no longer apparent following prolonged cocaine self-administration. Correlational analyses indicate that the association of H3K9me3 at D2 may be a critical substrate underlying the propensity to relapse. These findings suggest that low D2 mRNA levels in the nucleus accumbens core, likely mediated via epigenetic modifications, may render individuals more susceptible to cocaine addiction. In contrast, low FGF2 levels, which appear immutable even following prolonged cocaine exposure, may serve as a protective factor.