Escalated Oxycodone Self-Administration and Punishment: Differential Expression of Opioid Receptors and Immediate Early Genes in the Rat Dorsal Striatum and Prefrontal Cortex
Escalated Oxycodone Self-Administration and Punishment: Differential Expression of Opioid Receptors and Immediate Early Genes in the Rat Dorsal Striatum and Prefrontal Cortex
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DOI：
10.3389/fnins.2019.01392
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发表时间：
2020-01-09
影响因子：
4.3
通讯作者：
Cadet, Jean Lud
中科院分区：
文献类型：
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作者：
Blackwood, Christopher A.;McCoy, Michael T.;Cadet, Jean Lud
阿片类药物使用障碍(OUD)的特征是强迫服药，尽管有不良的生活后果。在这里，我们试图确定与羟考酮自我给药升级后给予或有足电击的行为影响相关的神经生物学后果。为了达到这些目标，Spraogue-Dawley大鼠接受了为期4周的自我给药训练，然后暴露于或有电击中。这一范式有助于将大鼠分为两种不同的行为表型：(1)减少杠杆挤压(电击敏感)的大鼠和(2)在或有惩罚期间继续杠杆挤压(抗电击)羟考酮的大鼠。在最后一次羟考酮加足底电击后2小时处死大鼠。解剖背侧纹状体和前额叶皮质，用于蛋白质印迹和RT-qPCR分析。羟考酮自身给药大鼠仅在背侧纹状体Mu和Kappa阿片受体蛋白的表达显著降低。然而，Delta阿片受体蛋白在两个脑区的表达均减少。RT-qPCR分析表明，休克敏感大鼠背侧纹状体c-fos、FosB、FRA2、JunB、Egr1和egr2mRNAs的表达显著降低(但在PFC中无明显变化)。在PFC中，Jund在两种表型中的表达均降低。然而，只有抗休克大鼠的PFC中egr3mRNA的表达增加。这些结果表明，与精神刺激剂和酒精类似，足部电击可以将增加羟考酮摄入量的大鼠一分为二，形成两种不同的行为表型。这些动物在即刻早期基因的mRNA表达上也表现出显著的差异，主要是在背侧纹状体。抗休克大鼠PFC egr3表达的增加提示，egr3可能参与了厌恶条件下羟考酮相关记忆的持续。这种惩罚驱动的模型可能有助于确定在出现不良后果时持续服用羟考酮和戒酒的神经生物学基础。
Opioid use disorder (OUD) is characterized by compulsive drug taking despite adverse life consequences. Here, we sought to identify neurobiological consequences associated with the behavioral effects of contingent footshocks administered after escalation of oxycodone self-administration. To reach these goals, Sprague-Dawley rats were trained to self-administer oxycodone for 4 weeks and were then exposed to contingent electric footshocks. This paradigm helped to dichotomize rats into two distinct behavioral phenotypes: (1) those that reduce lever pressing (shock-sensitive) and (2) others that continue lever pressing (shock-resistant) for oxycodone during contingent punishment. The rats were euthanized at 2-h after the last oxycodone plus footshock session. The dorsal striata and prefrontal cortices were dissected for use in western blot and RT-qPCR analyses. All oxycodone self-administration rats showed significant decreased expression of Mu and Kappa opioid receptor proteins only in the dorsal striatum. However, expression of Delta opioid receptor protein was decreased in both brain regions. RT-qPCR analyses documented significant decreases in the expression of c-fos, fosB, fra2, junB, egr1, and egr2 mRNAs in the dorsal striatum (but not in PFC) of the shock-sensitive rats. In the PFC, junD expression was reduced in both phenotypes. However, egr3 mRNA expression was increased in the PFC of only shock-resistant rats. These results reveal that, similar to psychostimulants and alcohol, footshocks can dichotomize rats that escalated their intake of oxycodone into two distinct behavioral phenotypes. These animals also show significant differences in the mRNA expression of immediate early genes, mainly, in the dorsal striatum. The increases in PFC egr3 expression in the shock-resistant rats suggest that Egr3 might be involved in the persistence of oxycodone-associated memory under aversive conditions. This punishment-driven model may help to identify neurobiological substrates of persistent oxycodone taking and abstinence in the presence of adverse consequences.