Chronic SKF83959 induced less severe dyskinesia and attenuated L-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease.
SKF83959, a recently identified selective agonist of putative phosphoinositide-linked (PI-linked) D(1) dopamine (DA) receptor, is found to elicit excellent anti-parkinsonism effects in monkeys and rodents. In the present study, the effects of SKF83959 on L-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) were assessed in a unilateral 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease (PD). The results indicated that chronic L-DOPA (6 mg/kg) induced a progressive dyskinesia-like behavior in PD rats, whereas SKF83959 (0.5 mg/kg) elicited significantly less severe dyskinesia while exerts its anti-parkinsonian action effectively. Application of D(1) receptor, but not D(2), alpha or 5-HT receptor antagonist attenuated SKF83959-induced dyskinesia, indicating that a D(1) receptor-mediated events, assumed via PI-linked D(1) receptor. Interestingly, chronic co-administration of SKF83959 significantly reduced LID at no expanse of reduction in the anti-parkinsonian potency in PD rats. However, this anti-dyskinesia effect was not observed while SKF83959 was acutely administered in rats with established LID. This implies that chronic SKF83959 attenuated the development of dyskinesia. Immediate early gene FosB is previously reported to positively associate with dyskinesia. However, we found that the anti-dyskinesia effect of chronic SKF83959 was independent of FosB since SKF83959 produced stronger FosB expression in the lesioned striatum than that of L-DOPA while exerting its anti-dyskinesia action. The present data demonstrated that SKF83959 reduces LID by attenuating the development of dyskinesia; the underlying signaling pathway for the anti-dyskinesia action of SKF83959 appears not to depend on FosB.
Zhang
Hai
H
Hubei Provincial Key Laboratory for Neural Diseases, Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Ma
Liqun
L
Wang
Fang
F
Chen
Jianguo
J
Zhen
Xuechu
X
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000009:adverse effects / Q000031:analogs & derivatives*; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000009:adverse effects*; D018492:Dopamine Antagonists / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D009068:Movement / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000008:administration & dosage; D013134:Spiperone / Q000008:administration & dosage; D013565:Sympatholytics / Q000633:toxicity; D013997:Time Factors
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D016760:Proto-Oncogene Proteins c-fos; D012702:Serotonin Antagonists; D013565:Sympatholytics; D007980:Levodopa; D013134:Spiperone; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C080703:SK&F 83959; D016627:Oxidopamine