Systemic administration of an mGluR5 antagonist, but not unilateral subthalamic lesion, counteracts l-DOPA-induced dyskinesias in a rodent model of Parkinson's disease.
Altered glutamatergic neurotransmission is central to the expression of Parkinson's disease (PD) symptoms and may underlie l-DOPA-induced dyskinesias. Drugs acting on glutamate metabotropic receptors (mGluR) of group I can modulate subthalamic nucleus (STN) overactivity, which plays a pivotal role in these phenomena, and may counteract dyskinesias. To address these issues, we investigated the effects of a 3-week treatment with mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), or of a subthalamic lesion, on abnormal involuntary movements (AIMs) and associated striatal expression of transcription factor FosB/Delta FosB caused by chronic l-DOPA administration, in rats with a nigrostriatal lesion. MPEP virtually abolished AIMs and reduced, dramatically, striatal expression of FosB/Delta FosB. Reduced FosB/Delta FosB expression, coupled with nonsignificant reduction of AIMs, was also observed in STN-lesioned rats. Our data confirm the role of glutamatergic neurotransmission in the pathogenesis of dyskinesias and the potential of mGluR5 antagonists in the treatment of l-DOPA-induced dyskinesias.
Levandis
Giovanna
G
Laboratory of Functional Neurochemistry, Interdepartmental Research Center for Parkinsons's Disease (CRIMP), IRCCS C. Mondino, Pavia, Italy.
Bazzini
Eleonora
E
Armentero
Marie-Thérèse
MT
Nappi
Giuseppe
G
Blandini
Fabio
F
D018663:Adrenergic Agents / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology* / Q000601:surgery; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects* / Q000627:therapeutic use; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011725:Pyridines / Q000009:adverse effects* / Q000627:therapeutic use; D051381:Rats; D020531:Subthalamic Nucleus / Q000293:injuries / Q000502:physiology*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D018691:Excitatory Amino Acid Antagonists; C483820:Fosb protein, rat; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D007980:Levodopa; C121465:6-methyl-2-(phenylethynyl)pyridine; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase