Gołembiowska K, Konieczny J, Ossowska K, Wolfarth S
Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Amino Acids. 2002;23(1-3):199-205. doi: 10.1007/s00726-001-0129-z.
Degeneration of dopaminergic nigrostriatal neurons is a primary cause of Parkinson's disease. Oxidative stress, excitotoxicity and mitochondrial failure are thought to be key mechanisms responsible for degeneration of dopaminergic cells. We found that the selective antagonist of the mGluR5 subtype MPEP in a dose of 5 mg/kg diminished basal and veratridine (100 microM)-stimulated dopamine release in rat striatum in an in vivo model of microdialysis. In contrast, MPEP given intrastriatally in a high concentration (500 microM) enhanced the striatal extracellular concentration of dopamine. DCG-IV (100 microM), a non-selective agonist of group II mGluRs, inhibited the veratridine-stimulated striatal dopamine release. In an animal model of neuroxicity in vivo, methamphetamine (5 x 10 mg/kg, injected at 2 h intervals) produced deficits in the striatal content of dopamine and its metabolites DOPAC and HVA 72 h after the treatment. MPEP (5 x 5 mg/kg) given before each methamphetamine injection reversed the decrease in the striatal content of dopamine and diminished the methamphetamine-induced dopamine outflow from nigrostriatal terminals. It is concluded that the MPEP-produced blockade of mGluR5 situated on dopaminergic cells, or the suppression of glutamate release in the subthalamic nucleus or substantia nigra pars reticulata may directly and indirectly cause a decrease in striatal dopamine release. However, inhibitory effect of DCG-IV on dopamine release can be induced by attenuation of excitatory input from corticostriatal terminals by activation of mGluR2/3. Regulation of dopamine carriers by MPEP, an antagonist of group I mGluRs may be responsible for the reversal of toxicity induced by methamphetamine.
多巴胺能黑质纹状体神经元变性是帕金森病的主要病因。氧化应激、兴奋性毒性和线粒体功能衰竭被认为是导致多巴胺能细胞变性的关键机制。我们发现，在微透析的体内模型中，剂量为5mg/kg的mGluR5亚型选择性拮抗剂MPEP可减少大鼠纹状体中基础和藜芦碱（100μM）刺激的多巴胺释放。相比之下，高浓度（500μM）脑内注射MPEP可提高纹状体细胞外多巴胺浓度。II组mGluRs的非选择性激动剂DCG-IV（100μM）可抑制藜芦碱刺激的纹状体多巴胺释放。在体内神经毒性动物模型中，甲基苯丙胺（5×10mg/kg，每隔2小时注射一次）在治疗后72小时导致纹状体中多巴胺及其代谢产物DOPAC和HVA含量降低。每次甲基苯丙胺注射前给予MPEP（5×5mg/kg）可逆转纹状体中多巴胺含量的降低，并减少甲基苯丙胺诱导的黑质纹状体终末多巴胺外流。得出的结论是，MPEP对多巴胺能细胞上mGluR5的阻断，或对丘脑底核或黑质网状部谷氨酸释放的抑制可能直接或间接导致纹状体多巴胺释放减少。然而，DCG-IV对多巴胺释放的抑制作用可能是通过激活mGluR2/3减弱皮质纹状体终末的兴奋性输入诱导的。I组mGluRs拮抗剂MPEP对多巴胺载体的调节可能是甲基苯丙胺诱导毒性逆转的原因。
