Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA.
Addict Biol. 2013 May;18(3):480-95. doi: 10.1111/j.1369-1600.2012.00470.x. Epub 2012 Jul 15.
Neuroadaptations in the ventral striatum (VS) and ventral midbrain (VMB) following chronic opioid administration are thought to contribute to the pathogenesis and persistence of opiate addiction. In order to identify candidate genes involved in these neuroadaptations, we utilized a behavior-genetics strategy designed to associate contingent intravenous drug self-administration with specific patterns of gene expression in inbred mice differentially predisposed to the rewarding effects of morphine. In a Yoked-control paradigm, C57BL/6J mice showed clear morphine-reinforced behavior, whereas DBA/2J mice did not. Moreover, the Yoked-control paradigm revealed the powerful consequences of self-administration versus passive administration at the level of gene expression. Morphine self-administration in the C57BL/6J mice uniquely up- or down-regulated 237 genes in the VS and 131 genes in the VMB. Interestingly, only a handful of the C57BL/6J self-administration genes (<3%) exhibited a similar expression pattern in the DBA/2J mice. Hence, specific sets of genes could be confidently assigned to regional effects of morphine in a contingent- and genotype-dependent manner. Bioinformatics analysis revealed that neuroplasticity, axonal guidance and micro-RNAs (miRNAs) were among the key themes associated with drug self-administration. Noteworthy were the primary miRNA genes H19 and micro-RNA containing gene (Mirg), processed, respectively, to mature miRNAs miR-675 and miR-154, because they are prime candidates to mediate network-like changes in responses to chronic drug administration. These miRNAs have postulated roles in dopaminergic neuron differentiation and mu-opioid receptor regulation. The strategic approach designed to focus on reinforcement-associated genes provides new insight into the role of neuroplasticity pathways and miRNAs in drug addiction.
慢性阿片类药物给药后腹侧纹状体（VS）和腹侧中脑（VMB）的神经适应性被认为有助于阿片类药物成瘾的发病机制和持续存在。为了确定参与这些神经适应性的候选基因，我们利用了一种行为遗传学策略，该策略旨在将 contingent 静脉内药物自我给药与特定的基因表达模式相关联，这些模式在对吗啡奖赏作用具有不同易感性的近交小鼠中。在 Yoked-control 范式中，C57BL/6J 小鼠表现出明显的吗啡强化行为，而 DBA/2J 小鼠则没有。此外，Yoked-control 范式揭示了自我给药与被动给药在基因表达水平上的强大后果。在 C57BL/6J 小鼠中，吗啡自我给药独特地上调了 VS 中的 237 个基因和 VMB 中的 131 个基因。有趣的是，只有少数 C57BL/6J 自我给药基因（<3%）在 DBA/2J 小鼠中表现出相似的表达模式。因此，可以有信心地将特定的基因集分配给依赖于条件和基因型的吗啡的区域性影响。生物信息学分析表明，神经可塑性、轴突导向和 micro-RNAs（miRNAs）是与药物自我给药相关的关键主题之一。值得注意的是，初级 miRNA 基因 H19 和包含 micro-RNA 的基因（Mirg）分别加工成熟 miRNA miR-675 和 miR-154，因为它们是介导对慢性药物给药反应的网络样变化的主要候选物。这些 miRNAs 在多巴胺能神经元分化和 mu-阿片受体调节中具有假定作用。旨在关注强化相关基因的策略为神经可塑性途径和 miRNAs 在药物成瘾中的作用提供了新的见解。
