Metabotropic glutamate mGluR5 receptor blockade opposes abnormal involuntary movements and the increases in glutamic acid decarboxylase mRNA levels induced by l-DOPA in striatal neurons of 6-hydroxydopamine-lesioned rats.
The present study examined the effect of a subchronic systemic administration of the glutamate metabotropic mGluR5 receptor antagonist MPEP on l-DOPA-induced dyskinesias and striatal gene expression in adult rats with a unilateral 6-OHDA lesion of dopamine neurons. The daily systemic administration of l-DOPA for 2 weeks induced a gradual increase in limb dyskinesia and axial dystonia. The subchronic systemic co-administration of MPEP reduced the severity of limb dyskinesia and axial dystonia over the whole duration of l-DOPA treatment. Subchronic l-DOPA administration was paralleled by a significant increase in mRNA levels of the two isoforms of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67 and GAD65) and preprodynorphin (PPD). Single cell analysis on emulsion radioautographs indicated that l-DOPA-induced increases in GAD67 occurred predominantly in preproenkephalin-unlabeled striatonigral and, to a lesser extent, in preproenkephalin-labeled striatopallidal neurons. MPEP completely reversed the effects of l-DOPA on GAD67 and reduced the increases in GAD65 and PPD mRNA levels in striatonigral neurons. MPEP also reversed the small l-DOPA-induced increase in GAD67 mRNA levels in striatopallidal neurons. Altogether, the findings support the idea that the relative efficacy of mGluR5 receptor antagonists to oppose l-DOPA-induced abnormal involuntary movements involves an ability to oppose increases in GAD gene expression and GABA-mediated signaling in striatonigral and striatopallidal neurons. The results also confirm the potential usefulness of antagonists of mGluR5 receptors as adjuncts in the treatment of l-DOPA-induced dyskinesia in patients with Parkinson's disease.
Yamamoto
N
N
Department of Anatomy and Neurobiology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
Soghomonian
J-J
JJ
D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000503:physiopathology; D015259:Dopamine Agents / Q000009:adverse effects / Q000494:pharmacology; D004399:Dynorphins / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000503:physiopathology; D004421:Dystonia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D007980:Levodopa / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine / Q000633:toxicity; D011498:Protein Precursors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018663:Adrenergic Agents; D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D011498:Protein Precursors; D011725:Pyridines; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C036448:pre-prodynorphin; D007980:Levodopa; D004399:Dynorphins; C121465:6-methyl-2-(phenylethynyl)pyridine; D016627:Oxidopamine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2