L-DOPA-induced dyskinesia in the intrastriatal 6-hydroxydopamine model of parkinson's disease: relation to motor and cellular parameters of nigrostriatal function.
In order to assess the role of striatal dopamine (DA) afferents in L-DOPA-induced dyskinesia, we have studied a large series of rats sustaining 2, 3, or 4 unilateral injections of 6-hydroxydopamine (6-OHDA) in the lateral striatum. This type of lesion produced a dose-dependent depletion of DA fibers in the caudate-putamen, which was most pronounced in the lateral aspects of this structure. An additional group of rats was injected with 6-OHDA in the medial forebrain bundle to obtain complete DA denervation on one side of the brain. During a course of chronic L-DOPA treatment, rats with intrastriatal 6-OHDA lesions developed abnormal involuntary movements (AIMs), which mapped onto striatal domains exhibiting at least approximately 90% denervation, as judged by DA transporter autoradiography. The denervated areas showed local upregulation of preproenkephalin and prodynorphin mRNA, and FosB-like immunoreactivity, which were highly correlated with the rats' AIM scores. When compared to completely DA-denervated animals, the rats with intrastriatal 6-OHDA lesions showed an overall lower incidence, lower severity and different topographic distribution of AIMs. The involvement of proximal limb and axial muscles in the abnormal movements was proportional to the spreading of the lesion from lateral towards medial aspects of the caudate-putamen. Locomotive AIMs were only seen in rats with complete lesions, but not in any of the animals with intrastriatal 6-OHDA (which showed > 5% DA fiber sparing in the medial striatum). Intrastriatally 6-OHDA-lesioned rats had a larger therapeutic window for L-DOPA than did rats with complete bundle lesions, since they exhibited an overall lower predisposition to dyskinesia but a similar degree of drug-induced motor improvement in a test of forelimb stepping. Our results are the first to demonstrate that selective and partial DA denervation in the sensorimotor part of the striatum can confer cellular and behavioral supersensitivity to L-DOPA, and that the phenomenology of L-DOPA-induced rat AIMs can be accounted for by the topography of DA denervation within the caudate-putamen.
Winkler
Christian
C
Department of Physiological Sciences, Neurobiology Division, Wallenberg Neuroscience Center, Lund University, BMC A11, S-221 84, Lund, Sweden.
Kirik
Deniz
D
Björklund
Anders
A
Cenci
M Angela
MA
D000344:Afferent Pathways / Q000503:physiopathology; D000818:Animals; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D001522:Behavior, Animal / Q000187:drug effects*; D015415:Biomarkers; D001931:Brain Mapping; D002421:Caudate Nucleus / Q000473:pathology; D003342:Corpus Striatum / Q000503:physiopathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D004745:Enkephalins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D007091:Image Processing, Computer-Assisted; D007980:Levodopa / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics; D016627:Oxidopamine / Q000008:administration & dosage / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos; D011699:Putamen / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013378:Substantia Nigra / Q000503:physiopathology*; D013563:Sympathectomy, Chemical; D014157:Transcription Factors
D001426:Bacterial Proteins; D015415:Biomarkers; D004745:Enkephalins; C483820:Fosb protein, rat; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D007980:Levodopa; D016627:Oxidopamine; C033660:preproenkephalin; D004298:Dopamine