Chronic L-DOPA treatment differentially regulates gene expression of glutamate decarboxylase, preproenkephalin and preprotachykinin in the striatum of 6-hydroxydopamine-lesioned rat.
The effect of a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle in rats and subsequent L-DOPA treatment for eight weeks on preproenkephalin, preprotachykinin and glutamate decarboxylase (M(r) 67,000) gene expression in the striatum was investigated by in situ hybridization. A 6-hydroxydopamine lesion of the medial forebrain bundle markedly increased the level of preproenkephalin messenger RNA (+66%) and modestly elevated the level of glutamate decarboxylase (M(r) 67,000) messenger RNA (+36%) in the denervated striatum, but caused a decrease in the level of preprotachykinin messenger RNA (-54%) relative to the intact striatum and to sham-lesioned control animals. Treatment with L-DOPA (200 mg/kg/24 h) for eight weeks reduced but did not abolish the 6-hydroxydopamine lesion-induced elevation of preproenkephalin messenger RNA and slightly reduced the elevation of glutamate decarboxylase (M(r) 67,000) messenger RNA in denervated striatum relative to intact side and control groups. However, L-DOPA treatment almost completely reversed the decrease in preprotachykinin messenger RNA caused by 6-hydroxydopamine lesioning when compared to intact side and control groups. The effect of L-DOPA on the gene expression of preproenkephalin and glutamate decarboxylase (M(r) 67,000) differs from the increase in striatal enkephalin content and glutamate decarboxylase activity previously found following L-DOPA treatment. In contrast, L-DOPA reversed the changes in preprotachykinin messenger RNA, reflecting previously reported increases in substance P content. The findings provide new evidence that chronic L-DOPA treatment differentially affects direct striatonigral and indirect striatopallidal pathways at the molecular level.
Zeng
B Y
BY
Neurodegenerative Diseases Research Centre, King's College, London, U.K.
Jolkkonen
J
J
Jenner
P
P
Marsden
C D
CD
D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal / Q000187:drug effects; D002230:Carbidopa / Q000494:pharmacology; D004745:Enkephalins / Q000096:biosynthesis*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005968:Glutamate Decarboxylase / Q000096:biosynthesis*; D017403:In Situ Hybridization; D007980:Levodopa / Q000494:pharmacology*; D008969:Molecular Sequence Data; D017072:Neostriatum / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D015345:Oligonucleotide Probes; D016627:Oxidopamine / Q000494:pharmacology*; D011498:Protein Precursors / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015320:Tachykinins / Q000096:biosynthesis*
D004745:Enkephalins; D015345:Oligonucleotide Probes; D011498:Protein Precursors; D012333:RNA, Messenger; D015320:Tachykinins; C044206:preprotachykinin; D007980:Levodopa; D016627:Oxidopamine; C033660:preproenkephalin; D005968:Glutamate Decarboxylase; D002230:Carbidopa