Striatal fosB expression is causally linked with l-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson's disease.
Rats with unilateral dopamine-denervating lesions sustained a 3-week treatment with a daily l-DOPA dose that is in the therapeutic range for Parkinson's disease. In most of the treated animals, chronic l-DOPA administration gradually induced abnormal involuntary movements affecting cranial, trunk, and limb muscles on the side of the body contralateral to the lesion. This effect was paralleled by an induction of FosB-like immunoreactive proteins in striatal subregions somatotopically related to the types of movements that had been elicited by l-DOPA. The induced proteins showed both regional and cellular colocalization with prodynorphin mRNA. Intrastriatal infusion of fosB antisense inhibited the development of dyskinetic movements that were related to the striatal subregion targeted and produced a local specific downregulation of prodynorphin mRNA. These data provide compelling evidence of a causal role for striatal fosB induction in the development of l-DOPA-induced dyskinesia in the rat and of a positive regulation of prodynorphin gene expression by FosB-related transcription factors.
Andersson
M
M
Department of Physiological Sciences, University of Lund, Wallenberg Neuroscience Centre, Sölvegatan 17, Lund, 223 62, Sweden.
Hilbertson
A
A
Cenci
M A
MA
D000818:Animals; D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D015415:Biomarkers; D002452:Cell Count; D004195:Disease Models, Animal; D020820:Dyskinesias / Q000503:physiopathology*; D004745:Enkephalins / Q000235:genetics*; D005260:Female; D007980:Levodopa / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009410:Nerve Degeneration / Q000139:chemically induced; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000503:physiopathology*; D011498:Protein Precursors / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects; D014157:Transcription Factors; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects
D016375:Antisense Elements (Genetics); D001426:Bacterial Proteins; D015415:Biomarkers; D004745:Enkephalins; C483820:Fosb protein, rat; D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D007980:Levodopa; C033660:preproenkephalin