Effects of early vs. late initiation of levodopa treatment in hemiparkinsonian rats.
We investigated the effect of early vs. late initiation of levodopa treatment on dyskinetic movements, rotational behavior and molecular markers in hemiparkinsonian rats. Male Sprague-Dawley rats received a unilateral 6-hydroxydopamine (6-OHDA) administration in the nigrostriatal pathway. Rats were divided into three groups treated with: (i) levodopa (6 mg/kg) twice daily for 22 days starting at 4 weeks after 6-OHDA (Early group); (ii) levodopa at the same dose, regimen and duration but starting at 12 weeks after 6-OHDA (Late group), and (iii) saline starting at 4 weeks after 6-OHDA and continuing until the Late group finished treatment. Dyskinesias were quantified on days 1 and 22 of levodopa treatment. Striatal expression of preproenkephalin and preprodynorphin mRNAs, subthalamic cytochrome oxidase mRNA, and glutamate decarboxylase 67 mRNA in the pars reticulata of the substantia nigra was measured by in-situ hybridization. After 22 days of levodopa treatment, the percentage of rats showing dyskinesia was lower in the Early group than in the Late group (60% vs. 100%, respectively). No significant differences in total dyskinesia score were observed between both groups with the exception of the orolingual dyskinesias that were significantly less frequent in the Late group (P < 0.01). No significant differences were observed in the molecular markers between the Early and Late groups. Prompt initiation of levodopa treatment might be able to delay some of the basal ganglia molecular and circuitry changes underlying the development of dyskinesia but, once developed, they are behaviorally and molecularly similar to those appearing after late initiation of levodopa.
Marin
C
C
Laboratori de Neurologia Experimental, Area de Neurociències, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. cmarin@clinic.ub.es
Aguilar
E
E
Mengod
G
G
Cortés
R
R
Obeso
J A
JA
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004399:Dynorphins / Q000032:analysis / Q000235:genetics; D020820:Dyskinesias / Q000188:drug therapy / Q000503:physiopathology*; D003576:Electron Transport Complex IV / Q000032:analysis / Q000235:genetics; D004745:Enkephalins / Q000032:analysis / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000032:analysis / Q000235:genetics; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007980:Levodopa / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D011498:Protein Precursors / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology; D020531:Subthalamic Nucleus / Q000187:drug effects / Q000201:enzymology
D050483:Dopamine Plasma Membrane Transport Proteins; D004745:Enkephalins; D011498:Protein Precursors; D012333:RNA, Messenger; C036448:pre-prodynorphin; D007980:Levodopa; D004399:Dynorphins; D016627:Oxidopamine; C033660:preproenkephalin; D003576:Electron Transport Complex IV; D005968:Glutamate Decarboxylase