Chronic SKF83959 induced less severe dyskinesia and attenuated L-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease

Abstract

SKF83959, a recently identified selective agonist of putative phosphoinositide-linked (PI-linked) D₁ 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 D₁ receptor, but not D₂, α or 5-HT receptor antagonist attenuated SKF83959-induced dyskinesia, indicating that a D₁ receptor-mediated events, assumedly via PI-linked D₁ 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.

Introduction

The dopamine (DA) precursor, l-dihydroxyphenylalanine (L-DOPA), is the most effective drug for the treatment of Parkinson's disease (PD). However, chronic administration of L-DOPA is associated with the development of uncontrollable movements known as dyskinesia in a vast majority of patients (Nutt, 1990, Olanow et al., 2004, Fahn, 2005). Many patients have to terminate the therapy due to severe dyskinesia. Data from studies of monkeys and PD patients suggest that treatment with DA agonists is less potent at inducing dyskinesia than L-DOPA (Pearce et al., 1999, Rascol et al., 2000).

Recently, a novel DA receptor-coupled second messenger system other than the conventional G_α-adenylyl cyclase-cAMP pathway has been reported. This D₁-like DA receptor couples to G_q protein and stimulates phospholipase Cβ (PLCβ), resulting in hydrolysis of phosphoinositide (PI) (Undie et al., 1994, Deveney and Waddington, 1995, Pacheco and Jope, 1997, Clifford et al., 1999). SKF83959, a recently identified selective agonist for the putative PI-linked DA receptor, also acts as an antagonist of cAMP-coupled D₁ receptor (Andringa et al., 1999a, Jin et al., 2003, O'Sullivan et al., 2005, Waddington et al., 2005). It has been documented that SKF83959 has potent anti-parkinsonian effects on non-human primates and rodent models of PD, which may be mediated through activation of PLCβ (Gnanalingham et al., 1995a, Gnanalingham et al., 1995b, Gnanalingham et al., 1995c, Gnanalingham et al., 1995d, Andringa et al., 1999b, Zhen et al., 2005). However, little information is available on the relationship between the atypical D1 DA agonist SKF83959 and dyskinesia (Andringa et al., 1999b). In the present study, we employed an L-DOPA-induced dyskinesia (LID) model to study the role and mechanism of SKF83959 on dyskinesia in unilateral 6-hydroxydopamine (6-OHDA)-lesioned PD rats. The recently developed score system for abnormal involuntary movements (AIMs) was used to monitor the scope of dyskinesia (Cenci et al., 1998, Lee et al., 2000, Lundblad et al., 2002). The results demonstrated that chronic treatment with SKF83959 induced less severe dyskinesia than that of L-DOPA while exerting its powerful anti-parkinsonian action. Chronic administration of SKF83959 also attenuated the severity of LID. We further demonstrated that the SKF83959-mediatedanti-dyskinesia effect is independent of early response gene FosB.