Chronic L-DOPA treatment increases extracellular glutamate levels and GLT1 expression in the basal ganglia in a rat model of Parkinson's disease.
There is growing experimental evidence for the implication of glutamate-mediated mechanisms both in the pathophysiology of Parkinson's disease and in the development of dyskinesias with long-term administration of L-3,4-dihydroxyphenylalanine (L-DOPA). However, the impact of this treatment on glutamate transmission in the basal ganglia has been poorly investigated. In this study, we examined the effects of 6-hydroxydopamine-induced lesion of nigral dopamine neurons with or without subsequent chronic L-DOPA treatment on several parameters of glutamate system function in the rat striatum and substantia nigra pars reticulata. All the lesioned animals treated with L-DOPA developed severe dyskinesias. Extracellular glutamate levels, measured by microdialysis in freely moving conditions, and gene expression of the glial glutamate transporter GLT1, assessed by in situ hybridization, were unaffected by dopamine lesion or L-DOPA treatment alone, but were both markedly increased on the lesion side of rats with subsequent L-DOPA treatment. No change in the expression of the vesicular glutamate transporters vGluT1 and vGluT2 was measured in striatum. These data show that chronic L-DOPA treatment leading to dyskinesias increases basal levels of glutamate function in basal ganglia. The L-DOPA-induced overexpression of GLT1 may represent a compensatory mechanism involving astrocytes to limit glutamate overactivity and subsequent toxic processes.
Robelet
S
S
Interactions Cellulaires, Neurodégénérescence et Neuroplasticité, UMR 6186, 31 chemin Joseph Aiguier, 13402 Marseille cedex 20, France.
Melon
C
C
Guillet
B
B
Salin
P
P
Kerkerian-Le Goff
L
L
D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism; D004334:Drug Administration Schedule; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis*; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000096:biosynthesis*; D007980:Levodopa / Q000008:administration & dosage*; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D027342:Excitatory Amino Acid Transporter 2; D018698:Glutamic Acid; D007980:Levodopa