Relationship Between Parkinson's Disease And Metabotropic Glutamate Receptors

Parkinson's disease is characterized by a progressive degeneration of nigral dopamine neurons. According to current theories of functional anatomy of BG, an altered balance between dopamine- and glutamate-mediated neurotransmissions is thought to play a major role in the pathogenesis of PD. Because of the reduction of dopamine D2 receptor-mediated inhibition of striatopallidal neurons, glutamate pathways within the indirect circuit become overactive. Reduction of the overactivity of the indirect pathway, which generates from the striatopallidal neurons, this, is one of the goals of antiparkinsonian treatments. Such a reduction may be achieved by potentiating the dopaminergic neurotrasmission and/or by inhibiting the glutamatergic tone.L-Glutamate is the principal excitatory neurotransmitter of the central nervous system. Glu activates two types of receptors, the ligand-gated ion channels (iGlu) and G-protein coupled metabotropic glutamate (mGlu) receptors. Some studies suggest that excitoxic effect of glutamate mediated by iGluRs may be involved in the pathogenesis of PD. Antagonists of ionotropic glutamate receptors are reported to possess antiparkinsonian effects with undesirable side-effects, which greatly limited its clinical application.Metabotropic glutamate receptors are a family of G-protein-coupled receptors linked to multiple second messengers and modulation of ion channel functions in the nervous system. Molecular cloning has revealed the existence of eight distinct receptor subtypes, termed mGluRl-mGluRS, which are classified into three subgroups based on sequence similarities, pharmacological profiles and signal transduction pathways activated in heterologous systems. Group I receptors (mGluR1, 5) couple to phospholipase C and regulate neuronal excitability whereas group II (mGluR2, 3) and group III receptors (mGluR4, 6, 7, 8) inhibit adenylyl cyclase and modulate neurotransmitter release.With the recently developed agonists/antagonists that are relatively selective for mGluRs, many studies have performed over the last few years to define roles of mGluRs in the regulation of central nervous system functions. Abundant evidences suggest that mGluRs may be useful targets for therapeutic intervention in PD. But until now no neurobiochemistry study has reported the relationship between mGluRs and PD. The present study used in vivo microdialysis to examine the capacity of mGluRs subgroup-selective ligands to modulate the extracellular levels of dopamine and glutamate in the striatum of 6-OHDA lesioned rats. In this study, we also used cell model of PD to explore if mGluRs could induce neuroprotection against 6-OHDA induced neurotoxicity in PC 12 cells and the relationship between 6-OHDA neurotoxicity and glutamate excitoxicity.Part I. The regulation of transmitter level by metabotropic glutamate receptors in striatum of 6-hydroxydopamine-lesioned rats: in vivo microdialysis experimentsAIM: To examine the capacity of mGluRs subgroup-selective ligands to modulate the extracellular levels of dopamine and glutamate in the striatum of 6-OHDA lesioned rats.METHODS: Unilateral injections of 6-OHDA (8 ug/4 ul) were performed in the left nigrostriatal pathway by means of a Hamilton syringe. Three weeks after the lesion, the animals' ability to rotate in response to apomorphine (0.05 mg/kg subcutaneously, Sc) was tested. Only animals showing at least 7 turns/min in the last test were included in the study. 6-OHDA-lesioned rats were stereotaxically implanted with stainless steel guide cannula 2 mm above the upper boundaries of striatum. After a week's recovery, a dialysis probe was inserted through the guide cannula. Artificial cerebrospinal fluid was advanced through the probe via a BAS syringe pump. Various compounds were added in the artificial cerebrospinal fluid and perfused into the dorsal striatum through the dialysis probe. The concentration of dopamine and glutamate in dialysate samples was detected by HPLC.RESULTS: It was found that group I antagonist DL-AP3 do not cause any detecta...