Decreased expression of l-dopa-induced dyskinesia by switching to ropinirole in MPTP-treated common marmosets

Abstract

Current concepts suggest that pulsatile stimulation of dopamine receptors following l-dopa administration leads to priming for dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated primates, while continuous dopaminergic stimulation with long-acting dopamine agonists does not. We investigated whether l-dopa-induced dyskinesia is reduced by switching to a dopamine agonist. MPTP-treated marmosets received chronic treatment with l-dopa or ropinirole in doses producing equivalent motor activity and reversal of motor deficits. Administration of l-dopa led to the rapid onset of moderate to severe dyskinesia, whereas ropinirole produced only mild dyskinesia. Animals initially treated with l-dopa were switched to an equivalent dose of ropinirole and those treated with ropinirole were switched to an equivalent dose of l-dopa for 56 days. l-dopa-primed animals that were switched to ropinirole showed a trend towards a reduction of dyskinesia intensity, whereas animals initially treated with ropinirole and switched to l-dopa showed a trend toward increased dyskinesia intensity. A subsequent, acute l-dopa challenge reversed motor deficits and induced intense dyskinesia in both groups. This suggests that l-dopa leads to the priming and expression of dyskinesia, but that expression is not maintained when switching to a long-acting dopamine agonist. In contrast, dopamine agonists may prime for dyskinesia, but do not lead to its full expression.

Introduction

The long-term treatment of Parkinson's disease (PD) with l-dopa is complicated by the onset of dyskinesia in approximately 40% of the patient population (Ahlskog and Muenter, 2001, Obeso et al., 2000, Rascol et al., 2003). The priming process for the induction of dyskinesia is poorly understood, but once this has occurred it seems to be persistent, if not permanent, and not easily reversed (Agid et al., 1985, Bejjani et al., 2000). Priming in this context is used to describe the induction of dyskinesia in response to repeated treatment with l-dopa, that once established can be induced by subsequent treatment with l-dopa or a dopamine agonist. However, as discussed in this article, some dopamine agonists given chronically may not themselves induce dyskinesia, but on subsequent treatment with l-dopa involuntary movements rapidly appear. Dyskinesia can be suppressed by the use of NMDA antagonist drugs, such as amantadine, but only a proportion of patients tolerate effective doses (Cersosimo et al., 2000, Crosby et al., 2003). Currently, there are few pharmacological options for suppressing dyskinesia apart from a reduction in dopaminergic medication which adversely affects the relief of motor symptoms. Dyskinesia intensity can be reduced by continuous intravenous infusions of l-dopa or continuous intravenous or subcutaneous infusions of apomorphine (Manson et al., 2002, Kanovsky et al., 2002). This suggests that the manner of drug delivery may be key to the genesis and reversal of those mechanisms responsible for dyskinesia induction. Indeed, the risk of developing dyskinesia in newly diagnosed patients with PD is reduced by using long-acting dopamine agonists which produce continuous dopamine receptor stimulation, so mimicking the tonic stimulation occurring under normal physiological conditions (Inzelberg et al., 2003, Rascol et al., 2000). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated primates, the repeated administration of long-acting dopamine agonist drugs, such as ropinirole, bromocriptine, cabergoline or pergolide induces a lower intensity of dyskinesia compared to equivalent antiparkinsonian doses of l-dopa (Bedard et al., 1986, Pearce et al., 1998, Maratos et al., 2003, Nomoto et al., 1998). In addition, dyskinesia initially occurring as a result of prior l-dopa exposure can be suppressed by switching to a high dose of a dopamine agonist in those patients able to tolerate such treatment (Rascol et al., 2002). Similarly, in MPTP-treated primates, replacement of l-dopa by the long-acting dopamine agonist cabergoline gradually suppresses dyskinesia expression, although at the expense of some reduction in antiparkinsonian activity (Belanger et al., 2003).

Expression of dyskinesia as used in this study relates to involuntary movements induced by drug administration as a result of a previous period of priming which itself may or may not have induced discernible dyskinesia. This expression of dyskinesia is associated with alterations in the balance of activity between the indirect and direct striatal–pallidal output pathways leading to altered neurone firing in the subthalamic nucleus (Perez-Otano et al., 1992, Tel et al., 2002, Zeng et al., 2004). However, there is dispute over whether these changes are mediated through the striatal–external globus pallidus (GPe) indirect pathway, or through the striatal–internal globus pallidus (GPi) direct pathway (Bejjani et al., 2000, Bezard et al., 2001, Dunnett, 2003, Picconi et al., 2003). Current evidence suggests that priming may involve glutamatergic mechanisms mediated through NMDA receptors and involving abnormal storage of information in the cortico-striatal pathway (Calabresi et al., 2000b, Chase et al., 2000b, Chase and Oh, 2000a). A current concept of the phenomenon of priming is that it is initiated by l-dopa, but not by dopamine agonist drugs and that this explains the differences observed in dyskinesia induction in humans. However, this concept has received scant attention to date and it seems to contrast with the known ability of dopamine agonist drugs to induce dyskinesia in some patients with PD and to induce dyskinesia in some MPTP-treated primates (Maratos et al., 2001, Pearce et al., 1998, Smith et al., 2002, Rascol et al., 2000). In fact, the available information suggests that dopamine agonists do prime for dyskinesia induction but do not lead to its expression (Rascol et al., 2000, Smith et al., 2006).

In the current study, we have set out to examine in MPTP-treated common marmosets whether, in animals primed to show dyskinesia by exposure to l-dopa, switching to an equivalent dose of the dopamine D₂/D₃ receptor agonist ropinirole leads to reduced dyskinesia expression. We have also examined whether animals treated with the dopamine agonist are primed for dyskinesia expression when switched to l-dopa treatment. Due to the relative scarcity of animals at the time of this study only 4 animals were allotted to each group and it was decided that biochemical or histological analysis of brain tissue would not be performed. The results show that l-dopa and dopamine agonist drugs differ in the extent of expression of involuntary movements, but that dopamine agonists do prime for dyskinesia induction as these immediately appear on exposure to l-dopa.