Knockout of ERKI enhances cocaine-evoked immediate early gene expression and behavioral plasticity
Knockout of ERKI enhances cocaine-evoked immediate early gene expression and behavioral plasticity
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DOI：
10.1038/sj.npp.1301014
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发表时间：
2006-12-01
影响因子：
7.6
通讯作者：
Robinson, Terry E.
中科院分区：
文献类型：
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作者：
Ferguson, Susan M.;Fasano, Stefania;Robinson, Terry E.
可卡因在中脑边缘皮质脑区产生持久神经适应性的能力被认为会促进人类的觅药行为并导致成瘾。Ras调控的Raf - MEK - ERK蛋白激酶信号级联反应与可卡因在动物中的行为和神经生物学作用有关。然而，这些药理学研究无法确定ERK的两种主要异构体（ERK1和ERK2）在这些过程中的具体作用。我们在此报告，ERK1异构体的缺失（这会导致ERK2刺激依赖性信号传导增加）促进了可卡因诱导的精神运动敏化的发展以及对可卡因条件性位置偏好的获得。相反，ERK信号传导的药理学阻断减弱了对可卡因的精神运动敏化的发展。最后，在中脑边缘皮质脑区，可卡因诱发的基因表达在ERK1缺失的小鼠中增强。因此，ERK信号传导的改变既影响可卡因的神经生物学作用，也影响其产生持久的药物经验依赖性行为可塑性的能力。我们的研究结果表明，反复接触药物后ERK2信号传导增强可能促进可卡因诱导的可塑性形式的发展，而这种可塑性有助于成瘾。
The ability of cocaine to produce lasting neural adaptations in mesocorticolimbic brain regions is thought to promote drug seeking and facilitate addiction in humans. The Ras-controlled Raf-MEK-ERK protein kinase signaling cascade has been implicated in the behavioral and neurobiological actions of cocaine in animals. However, these pharmacological studies have not been able to determine the specific role of the two predominant isoforms of ERK (ERK1 and ERK2) in these processes. We report here that deletion of the ERK1 isoform, which leads to increased ERK2 stimulus-dependent signaling, facilitates the development of cocaine-induced psychomotor sensitization and the acquisition of a cocaine conditioned place preference. Conversely, pharmacological blockade of ERK signaling attenuates the development of psychomotor sensitization to cocaine. Finally, cocaine-evoked gene expression in mesocorticolimbic brain regions is potentiated in ERK1-deficient mice. Thus, alterations in ERK signaling influence both the neurobiological impact of cocaine and its ability to produce enduring forms of drug experience-dependent behavioral plasticity. Our results suggest that enhanced ERK2 signaling following repeated drug exposure may facilitate the development of forms of cocaine-induced plasticity that contribute to addiction.