Effect of methamphetamine neurotoxicity on learning-induced Arc mRNA expression in identified striatal efferent neurons.
Effect of methamphetamine neurotoxicity on learning-induced Arc mRNA expression in identified striatal efferent neurons.
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DOI：
10.1007/bf03033855
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发表时间：
2008-12
影响因子：
3.7
通讯作者：
Keefe, Kristen A.
中科院分区：
文献类型：
--
作者：
Daberkow, David P.;Riedy, Matthew D.;Kesner, Raymond P.;Keefe, Kristen A.
甲基苯丙胺滥用会导致纹状体多巴胺持久、部分耗尽和认知功能障碍。然而，部分多巴胺耗竭对效应立即早期基因Arc（活性调节的细胞内相关蛋白）表达的影响，已知其参与学习和记忆相关的突触修饰，迄今尚未研究。雄性Sprague-Dawley大鼠用甲基苯丙胺或生理盐水的神经毒性方案进行预处理。7周后，大鼠在T型迷宫上接受运动反应任务训练5天，然后在第5天进行逆转训练。在达到逆转任务标准后5 min处死大鼠，取出大脑并使用双标记荧光原位杂交技术检测背内侧纹状体中Arc和前脑啡肽原（PPE）mRNA的表达。用甲基苯丙胺预处理的大鼠在背内侧纹状体中平均（±SEM）损失54.4±7.9%的多巴胺。有趣的是，在甲基苯丙胺与盐水预处理的大鼠中，逆转试验与标准没有差异。然而，Arc mRNA在背内侧纹状体的表达减弱甲基苯丙胺预处理的动物，特别是在PPE阴性神经元。此外，甲基苯丙胺预处理的动物背内侧纹状体Arc mRNA表达和学习之间的相关性被取消。这些数据表明，甲基苯丙胺诱导的部分单胺损失与干扰诱导的效应立即早期基因弧在行为任务，特别是在PPE阴性（假定纹状体黑质）神经元，以及中断的背内侧纹状体和逆转学习的Arc mRNA表达之间的关系。
Methamphetamine abuse results in lasting, partial depletions of striatal dopamine and cognitive dysfunction. However, the effect of partial dopamine depletions on the expression of an effector immediate early gene, Arc (activity regulated, cytoskeletal-associated protein), known to be involved in synaptic modifications underlying learning and memory has heretofore not been examined. Male Sprague-Dawley rats were pretreated with a neurotoxic regimen of methamphetamine or saline. Seven weeks later, rats were trained in a motor-response task on a T-maze for five days, and then underwent reversal training on day five. Rats were sacrificed 5 min after reaching criterion on the reversal task, and the brains removed and processed using double-label fluorescent in situ hybridization for Arc and preproenkephalin (PPE) mRNA expression in the dorsomedial striatum. Rats pretreated with methamphetamine had an average (±SEM) 54.4±7.9% loss of dopamine in dorsomedial striatum. Interestingly, there was no difference in reversal trials to criterion in methamphetamine- vs. saline-pretreated rats. However, the expression of Arc mRNA in dorsomedial striatum was attenuated in methamphetamine-pretreated animals, particularly in PPE-negative neurons. Furthermore, the correlation between Arc mRNA expression in dorsomedial striatum and learning was abolished in methamphetamine-pretreated animals. These data suggest that methamphetamine-induced partial monoamine loss is associated with disrupted induction of the effector immediate early gene Arc during a behavioral task, particularly in PPE-negative (presumed striatonigral) neurons, as well as with disruption of the relation between Arc mRNA expression in dorsomedial striatum and reversal learning.