Kuntz-Melcavage Kara L, Brucklacher Robert M, Grigson Patricia S, Freeman Willard M, Vrana Kent E
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
BMC Neurosci. 2009 Aug 7;10:95. doi: 10.1186/1471-2202-10-95.
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.
许多基因表达研究探讨了药物暴露所诱导的变化，但很少有报告描述复发后持续存在的变化。在本研究中，对表现出海洛因寻求行为和目标导向行为的行为潜伏期的大鼠进行了一次消退训练（90分钟）后，进行了全基因组基因表达分析。作为目标导向行为的重要调节因子，内侧前额叶皮质（mPFC）是基因组分析的对象。大鼠在每天3小时的训练中接受海洛因自我给药训练，持续14天。在自我给药期结束后，将大鼠重新引入自我给药室进行90分钟的消退训练，在此期间它们可以寻求海洛因，但未得到海洛因。在强制戒断1天或14天后对各组进行消退训练，以证明行为潜伏期。
行为数据表明，在14天戒断期后，海洛因寻求行为和目标导向行为出现潜伏期（表达增加）。也就是说，在强制戒断14天后，当动物回到它们之前接受过海洛因的环境中时，表现出增强的药物寻求行为。尽管在这次消退训练期间它们没有得到药物，但这种药物寻求行为仍有所增加。进行了全基因组基因表达分析，并通过定量实时PCR（RT-qPCR）对结果进行了验证。微阵列鉴定出66个基因，与盐水处理的对照组相比，在14天戒断和90分钟消退训练后，其表达变化至少为1.4倍（p < 0.02）。RT-qPCR的正交验证表明bdnf、calb1、dusp5、dusp6、egr1、npy、rgs2有显著改变。
本体分析表明，经确认发生变化的几个基因对神经可塑性很重要，并且通过该作用可能影响学习和行为。药物寻求行为和对先前药物服用过程的记忆的重要性表明，这些基因可能对复发很重要。全基因组基因表达分析增加了对海洛因诱导变化的认识，并进一步突出了海洛因与其他滥用药物之间的相似性。
