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Dopamine trasporter reversal as a pathogenic mechanism for L-dopa induced dyskinesia Cheng, Christina

Abstract

L-dopa remains the most effective drug for improving motor symptoms of Parkinson's disease (PD). However, following long-term chronic treatment, the therapeutic effects of L-dopa are often accompanied by debilitating peak-dose dyskinesia. The mechanisms underlying L-dopa induced dyskinesia remain unknown. Rapid increases of dopamine (DA) in the severely DA denervated striatum are associated with L-dopa induced dyskinesia (Miller and Abercrombie, 1999). This DA efflux is believed to cause many post-synaptic changes that are associated with L-dopa induced dyskinesia (Olanow et al., 2000). Therefore, it is of interest to examine the underlying mechanisms of the L-dopa induced DA release. The objectives of the present experiments were to examine the role for the DA transporter (DAT) in mediating L-dopa-induced DA release. Firstly, systemic injection of a DAT antagonist, methylphenidate (MP) was used to assess the role of the DAT in L-dopa induced dyskinesia in chronically L-dopa treated animals. Results showed a dose-dependent effect of MP in the attenuation of L-dopa induced dyskinesia. Secondly, we investigated the functional mode of the DAT by examining the effects of MP pre-treatment on the L-dopa induced DA efflux and dyskinetic responses in three groups of rats 1) L-dopa-naive, 2) 1-week L-dopa treated, and 3) 3-week L-dopa treated, rats. MP pretreatment had no effect on L-dopa induced DA efflux in L-dopa naive, or 1 -week L-dopa treated animals. In contrast, systemic pretreatment of MP significantly attenuated the L-dopa induced DA response in 3-week treated rats, which was correlated with a similar decrease in L-dopa induced dyskinesia. The results from these experiments lend support to our hypothesis that reversal of the DAT through chronic L-dopa treatment contributes to the pathogenesis of L-dopa induced dyskinesia. Therefore, these findings suggest that the DAT is an important pharmacological target in the study and treatment of L-dopa induced dyskinesia.

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