Chronic treatment with the mGlu5R antagonist MPEP reduces the functional effects of the mGlu5R agonist CHPG in the striatum of 6-hydroxydopamine-lesioned rats: possible relevance to the effects of mGlu5R blockade in Parkinson's disease.
This study was designed to test whether chronic treatment with the metabotropic glutamate receptor 5 (mGlu5R) antagonist MPEP showed antiparkinsonian effects in rats unilaterally lesioned with 6-hydroxydopamine (6-OHDA) (a "classic" model of Parkinson's disease, PD), and to evaluate whether chronic MPEP influenced the functional properties and/or the expression of striatal mGlu5Rs. Wistar rats were lesioned with 6-OHDA and then treated with MPEP (3 mg/kg/day, i.p.) or its vehicle over 2 weeks. Chronic MPEP did not induce measurable antiparkinsonian effects, since no differences were found between MPEP- and vehicle-treated animals in the pattern of L-DOPA-induced contralateral rotations. In corticostriatal slices taken from animals chronically treated with MPEP, the functional effects of the mGlu5R agonist CHPG were significantly reduced in the lesioned vs. the intact side, while no changes were found in slices taken from vehicle-treated rats. The binding of [3H]MPEP to striatal membranes showed that neither the maximal number of binding sites (Bmax) nor the dissociation constant (Kd) were changed by the lesion and/or by chronic MPEP. While chronic MPEP did not potentiate L-DOPA-induced turning in a classical model of PD, its ability to reduce mGlu5R-associated signal could help to explain the neuroprotective/antiparkinsonian effects observed in other models of PD.
Domenici
Maria Rosaria
MR
Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Potenza
Rosa Luisa
RL
Martire
Alberto
A
Coccurello
Roberto
R
Pèzzola
Antonella
A
Reggio
Rosaria
R
Tebano
Maria Teresa
MT
Popoli
Patrizia
P
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D003714:Denervation; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D009924:Organ Culture Techniques; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy*; D010648:Phenylacetates / Q000494:pharmacology*; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors*; D013565:Sympatholytics; D014316:Tritium
C107349:2-chloro-5-hydroxyphenylglycine; D000978:Antiparkinson Agents; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D010648:Phenylacetates; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013565:Sympatholytics; D014316:Tritium; D007980:Levodopa; C121465:6-methyl-2-(phenylethynyl)pyridine; D016627:Oxidopamine; D005998:Glycine