Validation of the l-dopa-induced dyskinesia in the 6-OHDA model and evaluation of the effects of selective dopamine receptor agonists and antagonists.
Current treatments for Parkinson's disease (PD) rely on a dopamine replacement strategy and are reasonably effective, particularly in the early stages of the disease. However, chronic dopaminergic therapy is limited by the development of a range of side effects, including dyskinesia. This has led to a search for alternative treatments. Transplantation of foetal nigral dopamine neurons is a rational approach and many studies have shown that it can improve motor functions in parkinsonian rodents, primates and man. Recently, however, two clinical trials have reported an exacerbation of dyskinesias in some transplanted patients, raising concerns about the safety of the transplantation strategy. To study this issue, we have reproduced the l-dopa-induced dyskinesia model developed by Cenci et al. [M.A. Cenci, C.S. Lee, A. Bjorklund, l-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA, Eur. J. Neurosci. 10 (1998) 2694-2706] in the rat. We find that their abnormal involuntary movements rating scale is easy to apply and consistent to use. Moreover, the Schallert forelimb placing test has been used to assess l-dopa-induced recovery of function and we find that the rats continue to show good recovery on this test, even while they are exhibiting abnormal dyskinetic side effects. To further evaluate this model, we have studied the effects of selective dopamine receptor antagonists and agonists for D1, D2 and D3 receptors. Antagonists of all three receptors are able to block the l-dopa-induced dyskinesia without interfering with the beneficial effects of l-dopa on the placing test. This indicates that the effects of chronic l-dopa on recovery of parkinsonian symptoms and on induction of dyskinetic side effects can be dissociated, which may provide the basis for developing novel combination treatments, e.g. using grafts while blocking the unwanted adverse effects of the drugs.
Monville
Christelle
C
Cardiff University, School of Biosciences, Museum Avenue, Cardiff CF10 3US, UK. monvillec@cf.ac.uk
Torres
Eduardo M
EM
Dunnett
Stephen B
SB
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D004744:Enkephalin, Methionine / Q000378:metabolism; D005260:Female; D007980:Levodopa / Q000494:pharmacology*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism; D015203:Reproducibility of Results; D013565:Sympatholytics
D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D016760:Proto-Oncogene Proteins c-fos; D011954:Receptors, Dopamine; D013565:Sympatholytics; D007980:Levodopa; D004744:Enkephalin, Methionine; D016627:Oxidopamine