title: Nigrostriatal denervation does not affect glutamate transporter mRNA expression but subsequent levodopa treatment selectively increases GLT1 mRNA and protein expression in the rat striatum.
abstract: There is growing evidence that the loss of the nigrostriatal dopaminergic neurones induces an overactivity of the corticostriatal glutamatergic pathway which seems to be central to the physiopathology of parkinsonism. Moreover, glutamatergic mechanisms involving NMDA receptors have been shown to interfere with the therapeutical action of levodopa. Given the key role played by uptake processes in glutamate neurotransmission, this study examined the effects of nigrostriatal deafferentation and of levodopa treatment on the striatal expression of the glutamate transporters GLT1, GLAST and EAAC1 in the rat. No significant changes in striatal mRNA levels of these transporters were detected after either levodopa treatment (100 mg/kg; i.p., twice a day for 21 days) or unilateral lesion of the nigrostriatal pathway by intranigral 6-hydroxydopamine injection. In contrast, animals with the lesion subsequently treated with levodopa showed a selective increase (36%) in GLT1 mRNA levels in the denervated striatum versus controls. These animals also showed increased GLT1 protein expression, as assessed by immunostaining and western blotting. These data provide the first evidence that levodopa therapy may interfere with striatal glutamate transmission through change in expression of the primarily glial glutamate transporter GLT1. We further suggest that levodopa-induced GLT1 overexpression may represent a compensatory mechanism preventing neurotoxic accumulation of endogenous glutamate.
authors.affiliation: Functional and Cellular Neurobiology Laboratory, CNRS, Marseille Cedex, France.
authors.forename: J C
authors.initials: JC
authors.lastname: Liévens
authors.forename: P
authors.initials: P
authors.lastname: Salin
authors.forename: A
authors.initials: A
authors.lastname: Nieoullon
authors.forename: L
authors.initials: L
authors.lastname: Kerkerian-Le Goff
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D003714:Denervation; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis / Q000235:genetics*; D050580:Excitatory Amino Acid Transporter 3; D005260:Female; D005455:Fluorescent Antibody Technique; D050491:Glutamate Plasma Membrane Transport Proteins; D007980:Levodopa / Q000494:pharmacology*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D011859:Radiography; D051381:Rats; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D027981:Symporters
chemical_list: D027322:Amino Acid Transport System X-AG; D002352:Carrier Proteins; D015259:Dopamine Agents; D004745:Enkephalins; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; C493398:Slc1a1 protein, rat; C493392:Slc1a3 protein, rat; D027981:Symporters; D007980:Levodopa; C033660:preproenkephalin; D004298:Dopamine