Dopamine D3 receptor stimulation underlies the development of L-DOPA-induced dyskinesia in animal models of Parkinson's disease.
Development of L-DOPA-induced dyskinesia (LID) remains a major problem in the long-term treatment of Parkinson's disease (PD). Sensitization to L-DOPA correlates with ectopic expression of D3 dopamine receptors in the striatum, implicating D3 receptors in development of LID. We demonstrate that the selective D3 antagonist S33084 abolishes development of LID over 30 days in MPTP-lesioned marmosets without effecting the anti-parkinsonian actions of L-DOPA. Furthermore, following a 14 day washout, when challenged with L-DOPA in the absence of S33084, these animals continued to exhibit reduced LID. In the 6-OHDA-lesioned rat, S33084 similarly attenuated development of behavioural sensitization to L-DOPA. Additionally, L-DOPA-induced elevations in striatal pre-proenkephalin-A (PPE-A) (but not PPE-B, phospho[Thr(34)]DARPP-32, D1, and D2 receptor mRNA or D3 receptor levels) were reduced in S33084 treated animals. Our data suggest a role for D3 receptors in the development of LID and suggest that initiating L-DOPA treatment with a D3 antagonist may reduce the development of LID in PD.
Visanji
Naomi P
NP
Toronto Western Research Institute, 399 Bathurst Street, MC11-419, Toronto, Ontario M5T 2S8, Canada.
Fox
Susan H
SH
Johnston
Tom
T
Reyes
Gabriela
G
Millan
Mark J
MJ
Brotchie
Jonathan M
JM
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001578:Benzopyrans / Q000494:pharmacology; D002144:Callithrix; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000209:etiology* / Q000378:metabolism*; D004745:Enkephalins / Q000378:metabolism; D005260:Female; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D011498:Protein Precursors / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000978:Antiparkinson Agents; D001578:Benzopyrans; D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004745:Enkephalins; D011498:Protein Precursors; D011758:Pyrroles; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C408389:S 33084; D007980:Levodopa; D016627:Oxidopamine; C033660:preproenkephalin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine