Simultaneous microdialysis in striatum and substantia nigra suggests that the nigra is a major site of action of L-dihydroxyphenylalanine in the "hemiparkinsonian" rat.
L-DOPA is frequently used to relieve symptoms of Parkinson's disease (PD), but its use in patients with more advanced PD is complicated by on-off phenomena. We used simultaneous microdialysis of striatum and ipsilateral substantia nigra to characterize changes in extracellular fluid (ecf) levels of dopamine (DA) following systemic treatment with L-DOPA (25 mg/kg as methylester) in awake, normal rats and those with partial (less than 99%) or complete (greater than 99%) DA depleting unilateral lesions of the nigrostriatal pathway (nsp). In normal rats, nigral ecf DA rose 17-fold above baseline after L-DOPA, compared to a 2.6-fold increase in normal striata. Striatal ecf DA rose equally after L-DOPA in all three groups, whereas peak nigral ecf DA in completely lesioned rats was three times that in normal or partially lesioned animals. Peak nigral ecf DA in completely lesioned rats exceeded striatal ecf DA in all groups by almost 2-fold. Activity after L-DOPA was biphasic ("hyperkinetic/bradykinetic") in completely lesioned but not in normal or partially lesioned animals, and the reduced activity occurred 2.5-4 h after L-DOPA at a time when both nigral and striatal ecf DA levels were still elevated. L-DOPA-induced increases in activity were predictable by greater elevations in nigral compared to striatal ecf DA in animals with complete lesions of the nigrostriatal pathway. Post-DOPA reduced activity might result from desensitization of synaptic events mediated by DA receptors; this may underlie DOPA-related on-off phenomena in patients with advanced PD.
Orosz
D
D
Department of Neurology, University of Virginia School of Medicine, Charlottesville 22908.
Bennett
J P
JP
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D003956:Dialysis; D004298:Dopamine / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism*; D008297:Male; D010300:Parkinson Disease / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013378:Substantia Nigra / Q000378:metabolism*
D007980:Levodopa; D004298:Dopamine