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 D-3 dopamine receptors in the striatum, implicating D-3 receptors in development of LID. We demonstrate that the selective D-3 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, D-1, and D-2 receptor mRNA or D-3 receptor levels) were reduced in S33084 treated animals. Our data suggest a role for D-3 receptors in the development of LID and suggest that initiating L-DOPA treatment with a D-3 antagonist may reduce the development of LID in PD. (C) 2008 Elsevier Inc. All rights reserved.