Pharmacological validation of a mouse model of l-DOPA-induced dyskinesia

Abstract

Dyskinesia (abnormal involuntary movements) is a common complication of l-DOPA pharmacotherapy in Parkinson's disease, and is thought to depend on abnormal cell signaling in the basal ganglia. Dopamine (DA) denervated mice can exhibit behavioral and cellular signs of dyskinesia when they are treated with l-DOPA, but the clinical relevance of this animal model remains to be established. In this study, we have examined the pharmacological profile of l-DOPA-induced abnormal involuntary movements (AIMs) in the mouse. C57BL/6 mice sustained unilateral injections of 6-hydroxydopamine (6-OHDA) in the striatum. The animals were treated chronically with daily doses of l-DOPA that were sufficient to ameliorate akinetic features without inducing overt signs of dyskinesia upon their first administration. In parallel, other groups of mice were treated with antiparkinsonian agents that do not induce dyskinesia when administered de novo, that is, the D2/D3 agonist ropinirole, and the adenosine A2a antagonist KW-6002.

During 3 weeks of treatment, l-DOPA-treated mice developed AIMs affecting the head, trunk and forelimb on the side contralateral to the lesion. These movements were not expressed by animals treated with ropinirole or KW-6002 at doses that improved forelimb akinesia. The severity of l-DOPA-induced rodent AIMs was significantly reduced by the acute administration of compounds that have been shown to alleviate l-DOPA-induced dyskinesia both in parkinsonian patients and in rat and monkey models of Parkinson's disease (amantadine, −47%; buspirone, −46%; riluzole, −33%). The present data indicate that the mouse AIMs are indeed a functional equivalent of l-DOPA-induced dyskinesia.

Introduction

Dyskinesia (abnormal involuntary movements) is a common complication of l-DOPA pharmacotherapy in Parkinson's disease (PD), affecting up to 80% of the patients within a few years from treatment onset (Obeso et al., 2000a). The most common form of dyskinesia consists in a combination of dystonic and choreiform movements occurring at the time when l-DOPA is providing the maximal relief of parkinsonian symptoms (“on” dyskinesias; Marconi et al., 1994). Several lines of evidence concur to suggest that l-DOPA-induced dyskinesia results from a pulsatile stimulation of brain dopamine (DA) receptors, triggering a complex cascade of molecular and synaptic alterations within the basal ganglia (Chase, 1998, Bezard et al., 2001, Picconi et al., 2003). Knowledge of the plastic changes that prime the basal ganglia for a dyskinetic motor response to l-DOPA would be greatly advanced by the availability of a dyskinesia model in mice, which lend themselves to genetic manipulation of specific molecular and synaptic components. In a recent study (Lundblad et al., 2004), we have shown that unilaterally 6-hydroxydopamine (6-OHDA) lesioned mice treated with l-DOPA exhibit abnormal movements similar to those described in a validated model of l-DOPA-induced dyskinesia in the rat (for review, see Cenci et al., 2002b). Mice that develop abnormal movements under l-DOPA show striatal upregulation of ΔFosB-like immunoreactivity and prodynorphin mRNA, two well-established markers of maladaptive molecular plasticity in other animal models of l-DOPA-induced dyskinesia (Andersson et al., 1999, Doucet et al., 1996). These results suggest that it is possible to simulate l-DOPA-induced dyskinesia in the mouse, but do not provide any information on the predictive validity and clinical relevance of the mouse dyskinesia model.

In this study, we compared the evolution of abnormal movements in 6-OHDA-lesioned mice treated chronically with either l-DOPA or other antiparkinsonian drugs that produce little or no dyskinesia when given de novo. The two antiparkinsonian drugs used were the D2/D3 receptor agonist, ropinirole (Rascol et al., 2000), and the adenosine A2a receptor antagonist, KW-6002 (Kanda et al., 1998). Furthermore, we tested the effects of several substances that had been shown to reduce the severity of l-DOPA-induced dyskinesia in both PD patients and rat and monkey models of PD. The substances tested here were the glutamate NMDA receptor antagonist, amantadine (Crosby et al., 2003); the glutamate release-inhibitor, riluzole (Merims et al., 1999) and Lundblad and Cenci, unpublished); the 5 HT-1A receptor antagonist, buspirone (Bonifati et al., 1994, Dekundy et al., 2003). The acute antidyskinetic effect of these drugs was tested in animals that had already been primed for dyskinesia. The mouse abnormal movements were found to respond to the drugs and treatments under investigation in the same way as classical l-DOPA-induced “on” dyskinesias. Thus, the present results provide pharmacological validation to the concept that the induction of dyskinetic movements by l-DOPA is a well-conserved response from rodents to primates, although the physical manifestation of dyskinesia may have species-specific features.