| Summary: | 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. === Medicine, Faculty of === Graduate
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