title: The metabotropic glutamate receptor antagonist 2-methyl-6-(phenylethynyl) pyridine decreases striatal VGlut2 expression in association with an attenuation of L-DOPA-induced dyskinesias.
abstract: The striatal glutamatergic hyperactivity is considered critical in the development of levodopa-induced dyskinesias (LID) in Parkinson's disease (PD). Pharmacological antagonism of the metabotropic glutamate receptors (mGluRs), in particular, the subtype mGluR5, can inhibit the expression of dyskinesia in both rodent and nonhuman primate models of PD. However, the exact mechanisms underlying the mGluR5 antagonism effects are not completely known. The vesicular glutamate transporters (VGluts) are localized in the synaptic vesicles of the striatal glutamatergic axonal terminals. The effects of mGluR5 antagonism modulating VGlut1 and VGlut2, as selective markers for the corticostriatal and thalamostriatal pathways, respectively, are still unknown. We investigated the effects of the mGluR5 antagonist, 2-methyl-6-(phenylethynyl) pyridine (MPEP) on the striatal expression of VGlut1 and VGlut2 in levodopa-treated hemiparkinsonian rats. Male Sprague-Dawley rats received a unilateral 6-hydroxydopamine (6-OHDA) administration in the nigrostriatal pathway. Rats were treated with: (a) levodopa (12 mg/kg/day with benserazide 15 mg/kg, ip) + vehicle; (b) MPEP (1.5 mg/kg/day, ip) + vehicle; (c) levodopa + MPEP, or (d) saline for 10 days. Levodopa treatment induced dyskinesias and did not modify the striatal expression of either VGlut1 or VGlut2. The administration of MPEP significantly attenuated LID and decreased the levels of VGlut2, but not the VGlut1, in the striatum ipsilateral to the lesion (P < 0.05). Our results suggest that the effects of MPEP on LID might be mediated by a modulating effect on VGlut 2 expression.
authors.affiliation: Laboratori de Neurologia Experimental, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. cmarin@clinic.ub.es
authors.forename: C
authors.initials: C
authors.lastname: Marin
authors.forename: M
authors.initials: M
authors.lastname: Bonastre
authors.forename: E
authors.initials: E
authors.lastname: Aguilar
authors.forename: A
authors.initials: A
authors.lastname: Jiménez
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D007980:Levodopa / Q000633:toxicity; D008297:Male; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000502:physiology; D050599:Vesicular Glutamate Transport Protein 2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000978:Antiparkinson Agents; D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C493475:Slc17a6 protein, rat; D050599:Vesicular Glutamate Transport Protein 2; D007980:Levodopa; C121465:6-methyl-2-(phenylethynyl)pyridine