Rawls S M, McGinty J F
Department of Anatomy and Cell Biology, East Carolina University School of Medicine, Greenville, North Carolina 27858-4354, USA.
J Neurochem. 1997 Apr;68(4):1553-63. doi: 10.1046/j.1471-4159.1997.68041553.x.
L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC) reverses plasma membrane glutamate transporters and elevates extracellular glutamate levels in vivo. We investigated the possibility that L-trans-PDC-stimulated glutamate levels are mediated partially by increases in transsynaptic activity. Therefore, the degree to which L-trans-PDC-evoked glutamate levels depend on calcium, sodium-channel activation, and glutamate-receptor activation was investigated by infusing via reverse microdialysis (a) 0.1 mM calcium, (b) 1 microM tetrodotoxin, a selective blocker of voltage-dependent sodium channels, (c) R(-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a selective NMDA-receptor antagonist, or (d) LY293558, a selective alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate antagonist. In separate experimental groups, L-trans-PDC-evoked glutamate levels were reduced significantly by 55% in the presence of 0.1 mM calcium and by 46% in the presence of tetrodotoxin. Additionally, CPP and LY293558 significantly attenuated L-trans-PDC-evoked glutamate levels without altering basal glutamate levels. These data suggest that glutamate transporter reversal by L-trans-PDC initially elevates extracellular glutamate levels enough to stimulate postsynaptic glutamate receptors within the striatum. It is proposed that glutamate-receptor stimulation activates a positive feedback loop within the basal ganglia, leading to further glutamate release from corticostriatal and thalamostriatal afferents. Therefore, either extracellular striatal calcium reduction or tetrodotoxin perfusion leads to decreased action potential-dependent glutamate release from these terminals. In addition, blocking glutamate receptors directly reduces medium spiny neuronal firing and indirectly attenuates corticostriatal and thalamostriatal activity, resulting in an overall depression of L-trans-PDC-stimulated glutamate levels.
L-反式吡咯烷-2,4-二羧酸（L-反式-PDC）可逆转质膜谷氨酸转运体，并在体内升高细胞外谷氨酸水平。我们研究了L-反式-PDC刺激的谷氨酸水平部分由跨突触活动增加介导的可能性。因此，通过反向微透析注入（a）0.1 mM钙、（b）1 μM河豚毒素（一种电压依赖性钠通道的选择性阻滞剂）、（c）R(-)-3-(2-羧基哌嗪-4-基)丙基-1-膦酸（CPP，一种选择性NMDA受体拮抗剂）或（d）LY293558（一种选择性α-氨基-3-羟基-5-甲基异恶唑-4-丙酸拮抗剂），研究了L-反式-PDC诱发的谷氨酸水平对钙、钠通道激活和谷氨酸受体激活的依赖程度。在不同的实验组中，在存在0.1 mM钙的情况下，L-反式-PDC诱发的谷氨酸水平显著降低了55%，在存在河豚毒素的情况下降低了46%。此外，CPP和LY293558显著减弱了L-反式-PDC诱发的谷氨酸水平，而不改变基础谷氨酸水平。这些数据表明，L-反式-PDC导致的谷氨酸转运体逆转最初会使细胞外谷氨酸水平升高到足以刺激纹状体内的突触后谷氨酸受体。有人提出，谷氨酸受体刺激会激活基底神经节内的正反馈回路，导致皮质纹状体和丘脑纹状体传入纤维进一步释放谷氨酸。因此，细胞外纹状体钙减少或河豚毒素灌注会导致这些终末依赖动作电位的谷氨酸释放减少。此外，阻断谷氨酸受体直接降低中型多棘神经元的放电，并间接减弱皮质纹状体和丘脑纹状体活动，导致L-反式-PDC刺激的谷氨酸水平总体下降。
