Repeated L-dopa administration reduces the ability of dopamine storage and abolishes the supersensitivity of dopamine receptors in the striatum of intact rat.
The "wearing-off" phenomenon is a clinically recognized adverse effect of long-term L-DOPA therapy in Parkinson's disease. Several causes of this phenomenon have been proposed, but no direct evidence has yet been obtained. The present study was therefore conducted to investigate the effects of long-term L-DOPA administration on the dopamine system. We examined in rats the time course of the levels of L-DOPA and its metabolites in the serum and striatum, the activities of tyrosine hydroxylase and catechol O-methyltransferase, and the D1 and D2 dopamine receptor bindings in the striatum until 12 h after the final dose on the 28th day of repeated oral L-DOPA administration, and compared the results with those after a single L-DOPA administration. The results revealed that long-term L-DOPA administration induced (1) acceleration of DOPA absorption at the gut and the blood-brain barrier, (2) reduction of dopamine retention in the striatum, and (3) loss of "supersensitive response" of dopamine receptors. "Supersensitive response" induced by single L-DOPA administration was preceded by the increase of D1 messenger RNA. We suggest that these changes after long-term L-DOPA administration are causes of the "wearing-off" phenomenon in Parkinson's disease.
Department of Neurology, University of Tokyo, Japan.
M
M
Murata
I
I
Kanazawa
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D003342:Corpus Striatum / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000097:blood / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D011954:Receptors, Dopamine; D007980:Levodopa; D004295:Dihydroxyphenylalanine; D004298:Dopamine