Gene expression changes following extinction testing in a heroin behavioral incubation model.
Gene expression changes following extinction testing in a heroin behavioral incubation model.
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DOI：
10.1186/1471-2202-10-95
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发表时间：
2009-08-07
期刊：
影响因子：
2.4
通讯作者：
Vrana KE
中科院分区：
文献类型：
--
作者：
Kuntz-Melcavage KL;Brucklacher RM;Grigson PS;Freeman WM;Vrana KE
一些基因表达研究调查了药物暴露引起的变化，但很少有报告描述复发后持续存在的变化。在这项研究中，基因表达的全基因组分析是在大鼠消亡阶段(90分钟)后进行的，这些大鼠表现出寻求海洛因和目标定向行为的行为潜伏期。内侧前额叶皮质(MPFC)作为目标导向行为的重要调节器，是基因组分析的目标。训练大鼠每天给药3h，连续给药14d。给药结束后，将大鼠重新引入给药室进行90min的熄灭训练，在此过程中它们可以寻找海洛因，但没有得到任何海洛因。在非药物强制戒断1d或14d后对各组进行消退会议，以展示行为潜伏期。行为数据显示在14d戒断期后，海洛因寻找和目标导向行为的潜伏期(表达增加)。也就是说，在强制禁欲14天后，当动物返回到它们之前接受海洛因的环境时，它们表现出高度的寻求毒品行为。尽管在这次灭绝期间它们没有收到任何药物，但这种寻求毒品的行为还是发生了。进行全基因组基因表达分析，并用实时定量聚合酶链式反应(RT-qPCR)对结果进行验证。微阵列鉴定了66个基因，与生理盐水处理的对照组相比，在禁欲14天和90分钟的熄灭过程中，这些基因的表达至少发生了1.4倍的变化(p<；0.02)。RT-qPCR的正交验证显示，BDNF、calb1、dusp5、dusp6、egr1、NPY、rgs2发生了显著变化。本体论分析表明，被证实改变的几个基因对神经可塑性很重要，并可能通过这种作用影响学习和行为。寻找毒品的行为和对以前吸毒过程的记忆的重要性表明，这些基因可能对复发很重要。全球基因表达分析增加了对海洛因引起的变化的了解，并进一步突出了海洛因与其他滥用药物之间的相似之处。
A number of gene expression studies have investigated changes induced by drug exposure, but few reports describe changes that persist following relapse. In this study, genome-wide analysis of gene expression was conducted following an extinction session (90 min) in rats that expressed behavioral incubation of heroin-seeking and goal-directed behavior. As an important modulator of goal-directed behavior, the medial prefrontal cortex (mPFC) was the target of genomic analysis. Rats were trained to self-administer heroin during 3 h daily sessions for 14 d. Following the self-administration period, rats were reintroduced to the self-administration chambers for a 90-minute extinction session in which they could seek heroin, but received none. Extinction sessions were conducted on groups after either 1 d or 14 d of drug-free enforced abstinence to demonstrate behavioral incubation. Behavioral data demonstrated incubation (increased expression) of heroin-seeking and goal-directed behavior after the 14 d abstinent period. That is, following 14 d of enforced abstinence, animals displayed heightened drug-seeking behavior when returned to the environment where they had previously received heroin. This increased drug-seeking took place despite the fact that they received no drug during this extinction session. Whole genome gene expression analysis was performed and results were confirmed by quantitative real-time PCR (RT-qPCR). Microarrays identified 66 genes whose expression was identified as changed by at least 1.4 fold (p < 0.02) following 14 d of abstinence and the 90-minute extinction session compared to the saline treated controls. Orthogonal confirmation by RT-qPCR demonstrated significant alterations in bdnf, calb1, dusp5, dusp6, egr1, npy, rgs2. Ontological analysis indicates that several of the genes confirmed to be changed are important for neuroplasticity, and through that role may impact learning and behavior. The importance of drug-seeking behavior and memory of previous drug-taking sessions suggest that such genes may be important for relapse. The global gene expression analysis adds to the knowledge of heroin-induced changes and further highlights similarities between heroin and other drugs of abuse.
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