Dysfunction of the cortico-basal ganglia-cortical loop in a rat model of early parkinsonism is reversed by metabotropic glutamate receptor 5 antagonism.
This study examined the cellular correlates of the akinetic deficits produced in Wistar rats by discrete bilateral 6-hydroxydopamine (6-OHDA) striatal infusions in the dorsolateral striatum, mimicking the preferential denervation of the motor striatal territory in early symptomatic stage of Parkinson's disease (PD). Intraneuronal gene expression of cytochrome oxidase subunit I (COI), a metabolic index of neuronal activity, was increased in the subthalamic nucleus, substantia nigra pars reticulata and decreased in frontal cortical areas, but paradoxically unchanged in the striatum, globus pallidus, entopeduncular nucleus and ventrolateral thalamic nucleus. Neither preproenkephalin A nor preprotachykinin mRNA expression, markers of striatal projection neurons, were modified in the denervated striatal area despite 90% loss of dopamine (DA) terminals. Preproenkephalin A mRNA expression was however, decreased in the nondepleted striatal region, suggesting compensatory increase of dopamine tone from those spared areas. A chronic treatment with the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethylnyl)-pyridine (MPEP), which alleviated the akinetic disorders produced by the lesion, reversed the lesion-induced variations of COI gene expression, moderately increased this marker in the structures unaffected by the lesion and did not modify the striatal neuropeptides gene expression. These data suggest that the expression of akinetic deficits in early parkinsonism is associated with focused metabolic changes in the cortico-basal ganglia-cortical loop downstream of the striatum and pallidal complex.
Oueslati
Abid
A
Interactions Cellulaires, Neurodégénérescence et Neuroplasticité, UMR 6186, CNRS-Université de la Méditerranée, 31 chemin Joseph Aiguier, 13402 Marseille Cedex 20, France.
Breysse
Nathalie
N
Amalric
Marianne
M
Kerkerian-Le Goff
Lydia
L
Salin
Pascal
P
D000818:Animals; D001479:Basal Ganglia / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000503:physiopathology*; D003714:Denervation; D018765:Dopamine Uptake Inhibitors; D003576:Electron Transport Complex IV / Q000096:biosynthesis / Q000235:genetics; D004745:Enkephalins / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D017403:In Situ Hybridization; D008297:Male; D008454:Mazindol; D017072:Neostriatum / Q000378:metabolism; D009415:Nerve Net / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D011498:Protein Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013565:Sympatholytics; D015320:Tachykinins / Q000378:metabolism; D013788:Thalamus / Q000502:physiology
D018765:Dopamine Uptake Inhibitors; D004745:Enkephalins; D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D011498:Protein Precursors; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013565:Sympatholytics; D015320:Tachykinins; C044206:preprotachykinin; D016627:Oxidopamine; C033660:preproenkephalin; D008454:Mazindol; D003576:Electron Transport Complex IV