The role of striatal metabotropic glutamate receptors in degeneration of dopamine neurons: Review article

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 resposible for degeneration of dopaminergic cells. We found that the selective antagonist of the mGluR5 subtype MPEP in a dose of 5mg/kg diminshed basal and veratridine (100muM)-stimulated dopamine release in rat striatum in an in vivo model of micro-dialysis. In contrast, MPEP given intrastriatally in a high concentration (500muM) enhanced the striatal extracellular concentration of dopamine. DCG-IV (100muM), 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 10mg/kg, injected at 2h intervals) produced deficits in the striatal content of dopamine and its metabolites DOPAC and HVA 72h after the treatment. MPEP (5 X 5mg/kg) given before each methamphetamine injection reversed the decrease in the striatal content of dopamine and diminished the methamphetamine-induced doparnine 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 doparnine carriers by MPEP, an antagonist of group I mGluRs may be responsible for the reversal of toxicity induced by methamphetamine.