Stephans S E, Yamamoto B K
Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-5000.
Synapse. 1994 Jul;17(3):203-9. doi: 10.1002/syn.890170310.
The neurotoxic effects of methamphetamine (METH) on striatal dopaminergic neurons have been hypothesized to be mediated by excess dopamine (DA) release. In addition, N-methyl-D-aspartate (NMDA) receptor antagonists block METH-induced DA depletions. This suggests that glutamate also mediates the toxic effects of METH. The purpose of this study is to demonstrate that DA and glutamate efflux contribute to METH-induced neurotoxicity. In vivo microdialysis in rats was used to measure extracellular concentrations of striatal DA and glutamate following 3 injections of METH (10 mg/kg, i.p.), each injection given 2 hours apart. One week following the dialysis experiment, rats were sacrificed and the ventral lateral striata were assayed for DA content. Glutamate concentrations in the dialysate increased by over 4-fold after the third METH injection. In these same animals, striatal DA tissue content was significantly depleted. In separate groups of rats, pretreatment with haloperidol (2 mg/kg at the first METH injection) significantly increased METH-induced DA efflux. The haloperidol pretreatment attenuated the extracellular increase in glutamate produced by METH and blocked subsequent neurotoxicity to DA neurons. In contrast, pretreatment with the DA uptake blocker, GBR-12909 (10 mg/kg, 30 min before each METH injection) significantly attenuated the increased DA release produced by METH but did not change glutamate efflux. However, pretreatment with GBR-12909 did protect against the tissue content depletion of DA in the striatum. Based on these findings, it appears that increased DA and glutamate release in the striatum are important and possibly interact in the development of METH-induced neurotoxicity.
甲基苯丙胺（METH）对纹状体多巴胺能神经元的神经毒性作用被认为是由过量的多巴胺（DA）释放介导的。此外，N-甲基-D-天冬氨酸（NMDA）受体拮抗剂可阻断METH诱导的DA耗竭。这表明谷氨酸也介导了METH的毒性作用。本研究的目的是证明DA和谷氨酸外流促成了METH诱导的神经毒性。采用大鼠体内微透析技术，在3次注射METH（10mg/kg，腹腔注射）后，每次注射间隔2小时，测量纹状体DA和谷氨酸的细胞外浓度。透析实验1周后，处死大鼠并测定腹侧外侧纹状体的DA含量。第三次注射METH后，透析液中的谷氨酸浓度增加了4倍以上。在这些相同的动物中，纹状体DA组织含量显著减少。在另一组大鼠中，用氟哌啶醇（首次注射METH时为2mg/kg）预处理可显著增加METH诱导的DA外流。氟哌啶醇预处理减弱了METH引起的细胞外谷氨酸增加，并阻断了随后对DA神经元的神经毒性。相反，用DA摄取阻滞剂GBR-12909（每次注射METH前30分钟为10mg/kg）预处理可显著减弱METH引起的DA释放增加，但不改变谷氨酸外流。然而，GBR-12909预处理确实可防止纹状体中DA的组织含量减少。基于这些发现，纹状体中DA和谷氨酸释放的增加似乎很重要，并且可能在METH诱导的神经毒性发展过程中相互作用。
