Role of striatal L-DOPA in the production of dyskinesia in 6-hydroxydopamine lesioned rats.
We explored possible differences in the peripheral and central pharmacokinetics of L-DOPA as a basis for individual variation in the liability to dyskinesia. Unilaterally, 6-hydroxydopamine (6-OHDA) lesioned rats were treated chronically with L-DOPA for an induction and monitoring of abnormal involuntary movements (AIMs). Comparisons between dyskinetic and non-dyskinetic cases were then carried out with regard to plasma and striatal L-DOPA concentrations, tissue levels of dopamine (DA), DA metabolites, and serotonin. After a single intraperitoneal injection of L-DOPA, plasma L-DOPA concentrations did not differ between dyskinetic and non-dyskinetic animals, whereas peak levels of L-DOPA in the striatal extracellular fluid were about fivefold larger in the former compared with the latter group. Interestingly, the time course of the AIMs paralleled the surge in striatal L-DOPA levels. Intrastriatal infusion of L-DOPA by reverse dialysis concentration dependently induced AIMs in all 6-OHDA lesioned rats, regardless of a previous priming for dyskinesia. Steady-state levels of DA and its metabolites in striatal and cortical tissue did not differ between dyskinetic and non-dyskinetic animals, indicating that the observed difference in motor response to L-DOPA did not depend on the extent of lesion-induced DA depletion. These results show that an elevation of L-DOPA levels in the striatal extracellular fluid is necessary and sufficient for the occurrence of dyskinesia. Individual differences in the central bioavailability of L-DOPA may provide a clue to the varying susceptibility to dyskinesia in Parkinson's disease.
Department of Exp. Medical Science, Basal Ganglia Pathophysiology Unit, Lund University, Lund, Sweden.
Manolo
M
Carta
Hanna S
HS
Lindgren
Martin
M
Lundblad
Roberto
R
Stancampiano
Fabio
F
Fadda
M A
MA
Cenci
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000503:physiopathology; D045604:Extracellular Fluid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007980:Levodopa / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics*; D017551:Microdialysis; D008845:Microinjections; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D012701:Serotonin; D007980:Levodopa; D016627:Oxidopamine; D004298:Dopamine