Metabotropic glutamate 5 receptor blockade alleviates akinesia by normalizing activity of selective basal-ganglia structures in parkinsonian rats.
Glutamate overactivity within the basal ganglia has been shown to be central to the expression of motor symptoms in advanced stages of Parkinson's disease, and metabotropic glutamate receptors (mGluRs) represent promising targets for new therapeutic strategies in this pathology. Little is known, however, about the cellular and behavioral changes occurring in the early stages of the disease when dopamine depletion is moderate. Here, we report that rats with partial bilateral dopamine lesions exhibit akinetic deficits associated with dramatically increased neuronal metabolic activity in selective structures of the basal ganglia such as the subthalamic nucleus and the substantia nigra pars reticulata, but not in the entopeduncular nucleus. Furthermore, chronic treatment with the mGluR5 antagonist 2-methyl-6-(phenylethylnyl)-pyridine alleviated the akinesia and was associated with a normalization of the activity of these two overactive structures. These data stress the therapeutic potential of mGluR5 antagonists in the treatment of parkinsonian patients in the early stages of the disease.
Breysse
Nathalie
N
Laboratoire de Neurobiologie de la Cognition, Centre National de la Recherche Scientifique, 13402 Marseille, France.
Amalric
Marianne
M
Salin
Pascal
P
D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000235:genetics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000235:genetics; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology; D020531:Subthalamic Nucleus / Q000187:drug effects / Q000503:physiopathology
D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D007527:Isoenzymes; D011725:Pyridines; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C121465:6-methyl-2-(phenylethynyl)pyridine; D016627:Oxidopamine; D003576:Electron Transport Complex IV; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1