Effects of single and multiple treatments with L-dihydroxyphenylalanine (L-DOPA) on dopamine receptor-G protein interactions and supersensitive immediate early gene responses in striata of rats after reserpine treatment or with unilateral nigrostriatal lesions.
We studied effects of L-dihydroxyphenylalanine (L-DOPA) treatment in rats following reserpine treatment or unilateral 6-hydroxydopamine (6-OHDA) injections into medial forebrain bundle. Quantitative in situ hybridization for mRNA's coding for the zinc finger immediate early gene (IEG) zif/268 or Jun family IEG jun b revealed that single L-DOPA injections accentuated IEG expression 3- to 7-fold in the dopamine (DA)-depleted striatum. This increased IEG response did not derive from any alterations in DA receptor-G protein coupling, assayed by DA stimulation of 35S-guanosine-5' (gamma-thio) triphosphate (35S-GTP-gamma-S) binding to striatal sections. Reserpine treatment increased both basal and maximal striatal DA-stimulated 35S-GTP-gamma-S binding. The augmented IEG responses to single L-DOPA treatments involved dependency on both D1 and D2 receptors and acutely to N-methyl-D-aspartate (NMDA) channels. Repetitive L-DOPA treatments yielded persistently elevated (zif/268) or additionally up-regulated (jun b) IEG response in the denervated striatum and down-regulated IEG responses in the control striatum. Degraded L-DOPA responses and appearance of involuntary movements after chronic L-DOPA use in advanced Parkinson's disease may derive from these IEG changes.
Khan
S M
SM
Center for the Study of Neurodegenerative Diseases, and the Department of Neurology, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Smith
T S
TS
Bennett
J P
JP
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D015259:Dopamine Agents / Q000494:pharmacology*; D051766:Early Growth Response Protein 1; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D017874:Immediate-Early Proteins; D017403:In Situ Hybridization; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012110:Reserpine / Q000633:toxicity; D013378:Substantia Nigra / Q000187:drug effects*; D013565:Sympatholytics / Q000633:toxicity; D014157:Transcription Factors / Q000235:genetics; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D015259:Dopamine Agents; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D016755:Proto-Oncogene Proteins c-jun; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013565:Sympatholytics; D014157:Transcription Factors; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D007980:Levodopa; D012110:Reserpine; D016627:Oxidopamine; D019204:GTP-Binding Proteins