Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice
Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice
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DOI：
10.1016/j.biopsych.2005.06.006
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发表时间：
2006-01-01
影响因子：
10.6
通讯作者：
Yamada, K
中科院分区：
文献类型：
--
作者：
Kamei, H;Nagai, T;Yamada, K
背景最近的临床研究表明，长期使用甲基苯丙胺（METH）会导致长期认知障碍。为了阐明METH诱导的认知障碍的机制，我们研究了METH对小鼠认知功能的影响。方法：小鼠重复给予METH 7天，并使用新物体识别任务评估其认知功能。比较氯氮平和氟哌啶醇对甲基苯丙胺所致认知功能障碍的治疗作用。结果：METH反复处理可引起大鼠对新事物的认知障碍和行为敏感化。这些影响在停药后至少持续28天。氯氮平，而不是氟哌啶醇，减少甲基苯丙胺诱导的认知障碍。ERK 1/2的过度磷酸化被发现在暴露于新物体的小鼠的前额叶皮层中，但在用METH处理的小鼠中被消除。ERK 1/2的抑制通过微量注射PD 98059到前额叶皮层导致认知defiction.Conclusions：这些结果表明，反复METH治疗诱导认知障碍，这是与前额叶皮层的ERK 1/2通路的功能障碍。
Background Recent clinical studies have suggested that chronic use of methamphetamine (METH) induces long-term cognitive deficits. To clarify the mechanism of METH-induced cognitive impairment, we investigated the effect of METH on cognitive function in mice.Methods: Mice were repeatedly administered METH for 7 days, and their cognitive function was assessed using a novel-object recognition task. Therapeutic effects of clozapine and haloperidol on METH-induced cognitive impairment were investigated. Western blotting and specific inhibitors were employed to determine the role of extracellular signal-regulated kinase 1/2 (ERK1/2).Results: Repeated METH treatment induced an impairment of recognition of novel objects and behavioral sensitization. These effects persisted for at least 28 days after the drug withdrawal. Clozapine, but not haloperidol, reduced METH-induced cognitive impairment. Hyperphosphorylation of ERK1/2 was found in the prefrontal cortex of mice exposed to the novel objects, but was abolished in mice treated with METH. Inhibition of ERK1/2 by the microinjection of PD98059 into the prefrontal cortex resulted in cognitive impairment.Conclusions: These results suggest that repeated METH treatment induces cognitive impairment, which is associated with the dysfunction of the ERK1/2 pathway in the prefrontal cortex.