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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >High-dose methamphetamine acutely activates the striatonigral pathway to increase striatal glutamate and mediate long-term dopamine toxicity.
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High-dose methamphetamine acutely activates the striatonigral pathway to increase striatal glutamate and mediate long-term dopamine toxicity.

机译：大剂量甲基苯丙胺可急性激活纹状体神经通路，从而增加纹状体谷氨酸并介导长期的多巴胺毒性。

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Methamphetamine (METH) has been shown to increase the extracellular concentrations of both dopamine (DA) and glutamate (GLU) in the striatum. Dopamine, glutamate, or their combined effects have been hypothesized to mediate striatal DA nerve terminal damage. Although it is known that METH releases DA via reverse transport, it is not known how METH increases the release of GLU. We hypothesized that METH increases GLU indirectly via activation of the basal ganglia output pathways. METH increased striatonigral GABAergic transmission, as evidenced by increased striatal GAD65 mRNA expression and extracellular GABA concentrations in substantia nigra pars reticulata (SNr). The METH-induced increase in nigral extracellular GABA concentrations was D1 receptor-dependent because intranigral perfusion of the D1 DA antagonist SCH23390 (10 microm) attenuated the METH-induced increase in GABA release in the SNr. Additionally, METH decreased extracellular GABA concentrations in the ventromedial thalamus (VM). Intranigral perfusion of the GABA-A receptor antagonist, bicuculline (10 microm), blocked the METH-induced decrease in extracellular GABA in the VM and the METH-induced increase in striatal GLU. Intranigral perfusion of either a DA D1 or GABA-A receptor antagonist during the systemic administrations of METH attenuated the striatal DA depletions when measured 1 week later. These results show that METH enhances D1-mediated striatonigral GABAergic transmission (1), which in turn activates GABA-A receptors in the SNr (2), leading to a decrease in GABAergic nigrothalamic activity (3), an increase in corticostriatal GLU release (4), and a consequent long-term depletion of striatal DA content (5).
机译：甲基苯丙胺（METH）已显示会增加纹状体中多巴胺（DA）和谷氨酸（GLU）的细胞外浓度。假设多巴胺，谷氨酸或其组合作用可介导纹状体DA神经末梢损伤。尽管已知METH通过逆向运输释放DA，但不知道METH如何增加GLU的释放。我们假设METH通过激活基底节输出通路间接增加GLU。 METH增加了纹状体黑质GABA的能量传递，如网状黑质（SNr）中纹状体GAD65 mRNA表达和细胞外GABA浓度增加所证明的。 METH诱导的黑质细胞外GABA浓度增加是D1受体依赖性的，因为D1 DA拮抗剂SCH23390（10微米）的鼻内灌注减弱了SNr中METH引起的GABA释放增加。另外，METH降低了腹膜丘脑（VM）中细胞外GABA的浓度。 GABA-A受体拮抗剂bicuculline（10 microm）的鼻内灌注阻断了METH诱导的VM细胞外GABA减少和METH诱导的纹状体GLU增加。在METH全身给药期间，DA D1或GABA-A受体拮抗剂的鼻内灌注可减轻1周后测量的纹状体DA消耗。这些结果表明METH增强了D1介导的纹状体GABA能传递（1），继而激活了SNr中的GABA-A受体（2），导致GABA能黑藻丘脑活性降低（3），皮质泌尿道GLU释放增加（ 4），并因此长期消耗纹状体DA含量（5）。

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