Effect of the protein kinase C inhibitor, staurosporine, on the high dose of methamphetamine-induced behavioral sensitization to dizocilpine (MK-801)
Effect of the protein kinase C inhibitor, staurosporine, on the high dose of methamphetamine-induced behavioral sensitization to dizocilpine (MK-801)
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DOI：
10.1007/s00213-005-2145-2
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发表时间：
2005-06-01
影响因子：
3.4
通讯作者：
Koyama, T
中科院分区：
文献类型：
--
作者：
Fang, YR;Abekawa, T;Koyama, T
基本原理：在我们的初步研究中，2.5 mg/kg的甲基苯丙胺（METH）（但不是1.0 mg/kg）会诱导伏隔核（NAc）中谷氨酸水平延迟增加。我们假设，反复增加谷氨酸水平产生的行为敏感的选择性非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，地佐环平（MK-801），蛋白激酶C（PKC）的激活起着重要的作用，这种敏感。目的：进行本研究以确认由较高剂量的METH（2.5mg/kg）诱导的谷氨酸水平的延迟增加，并检查Straurosporine（一种PKC抑制剂）对较高剂量的METH诱导的地佐环平致敏的作用。方法：采用在体微透析技术研究METH对NAc细胞外谷氨酸水平的影响。通过使用红外传感器测量运动活动。结果：METH在2.5 mg/kg，但不是在1.0 mg/kg，诱导延迟谷氨酸水平的增加。星形孢菌素的急性给药不影响单次注射METH（2.5 mg/kg）的自发活动。重复METH给药（2.5 mg/kg，每隔一天一次，共5次）对地佐环平（0.2 mg/kg）（一种选择性非竞争性NMDA受体拮抗剂）的运动诱导作用产生了行为敏化。星形孢菌素（0.1毫克/公斤），给予120分钟后，每次METH治疗，抑制发展的行为敏感地佐环平。结论：这些结果表明，参与增加谷氨酸水平和激活的PKC在延迟诱导的突触和细胞可塑性的基础较高剂量的甲基诱导的行为敏感地佐环平。
Rationale: In our preliminary study, methamphetamine (METH) at 2.5 mg/kg, but not at 1.0 mg/kg, induced a delayed increase in glutamate levels in the nucleus accumbens (NAc). We hypothesize that repeated increases in glutamate levels produces behavioral sensitization to a selective uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801), and that an activation of protein kinase C (PKC) plays an important role for this sensitization. Objectives: This study was conducted to confirm delayed increases in glutamate levels induced by a higher dose of METH (2.5 mg/kg), and to examine the effect of straurosporine, a PKC inhibitor, on the higher dose of METH-induced sensitization to dizocilpine. Methods: The effects of METH on extracellular glutamate levels in the NAc were studied using in vivo microdialysis. Locomotor activity was measured by using an infrared sensor. Results: METH at 2.5 mg/kg, but not at 1.0 mg/kg, induced delayed increases in glutamate levels. The acute administration of staurosporine did not affect the locomotor activity by a single injection of METH (2.5 mg/kg). Repeated METH administrations (2.5 mg/kg, once in every other day, for five times) developed behavioral sensitization to the locomotion-inducing effect of dizocilpine (0.2 mg/kg), a selective uncompetitive NMDA receptor antagonist. Staurosporine (0.1 mg/kg), given 120 min later for every METH treatment, inhibited the development of behavioral sensitization to dizocilpine. Conclusions: These results suggest the involvement of increased glutamate levels and an activation of PKC in delayed-induced synaptic and cellular plasticity underlying the higher dose of METH-induced behavioral sensitization to dizocilpine.