Competitive and noncompetitive antagonists at N-methyl-D-aspartate receptors protect against methamphetamine-induced dopaminergic damage in mice.
Competitive and noncompetitive antagonists at N-methyl-D-aspartate receptors protect against methamphetamine-induced dopaminergic damage in mice.
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发表时间：
1991-02
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通讯作者：
P. Sonsalla;D. E. Riordan;R. Heikkila
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作者：
P. Sonsalla;D. E. Riordan;R. Heikkila
给实验动物施用甲基苯丙胺（METH）会导致黑质纹状体多巴胺能神经元受损。我们之前已经证明兴奋性氨基酸可能与这种神经毒性有关。例如，几种与 N-甲基-D-天冬氨酸 (NMDA) 受体相连的离子通道内的苯环己哌啶位点结合的化合物可以保护小鼠免受 METH 诱导的新纹状体酪氨酸羟化酶活性和多巴胺含量的丧失。本研究的目的是进一步表征兴奋性氨基酸在介导冰毒神经毒性作用中的作用。每 2 小时向小鼠注射 3 或 4 次冰毒 (10 mg/kg)，可导致新纹状体多巴胺含量 (80-84%) 和酪氨酸羟化酶活性 (65-74%) 大幅下降。两种非竞争性 NMDA 拮抗剂艾芬地尔和 SL 82.0715（25-50 mg/kg/注射）（均被认为与与 NMDA 受体复合物相关的多胺或西格玛位点结合）以及两种竞争性 NMDA 拮抗剂 CGS 19755（25-50 mg/kg/注射）和NPC 12626（150-300 mg/kg/注射）。此外，纹状体内输注 NMDA（0.1 微摩尔）会导致新纹状体多巴胺轻微但显着的损失，而在接受全身注射 METH 的小鼠中，这种损失会增强。这些研究结果强化了这样的假设：兴奋性氨基酸在 METH 诱导的黑质纹状体多巴胺能损伤中发挥着关键作用。
The administration of methamphetamine (METH) to experimental animals results in damage to nigrostriatal dopaminergic neurons. We have demonstrated previously that the excitatory amino acids may be involved in this neurotoxicity. For example, several compounds which bind to the phenyclidine site within the ion channel linked to the N-methyl-D-aspartate (NMDA) receptor protected mice from the METH-induced loss of neostriatal tyrosine hydroxylase activity and dopamine content. The present study was conducted to characterize further the role of the excitatory amino acids in mediating the neurotoxic effects of METH. The administration of three or four injections of METH (10 mg/kg) every 2 hr to mice produced large decrements in neostriatal dopamine content (80-84%) and in tyrosine hydroxylase activity (65-74%). A dose-dependent protection against these METH-induced decreases was seen with two noncompetitive NMDA antagonists, ifenprodil and SL 82.0715 (25-50 mg/kg/injection), both of which are thought to bind to a polyamine or sigma site associated with the NMDA receptor complex, and with two competitive NMDA antagonists, CGS 19755 (25-50 mg/kg/injection) and NPC 12626 (150-300 mg/kg/injection). Moreover, an intrastriatal infusion of NMDA (0.1 mumol) produced a slight but significant loss of neostriatal dopamine which was potentiated in mice that also received a systemic injection of METH. The results of these studies strengthen the hypothesis that the excitatory amino acids play a critical role in the nigrostriatal dopaminergic damage induced by METH.