Chronic treatment with
levodopa or
antipsychotics results in manifestation of side-effects such as
dyskinesia which correlates with changes in expression and function of receptors and signaling
proteins. Previous studies have suggested a role for the
dopamine D3 receptor in
Parkinson's disease (PD) and
tardive dyskinesia. Yet the expression and signaling function of D3 receptor in these disorders is not well understood. Here we tested the hypothesis that chronic
levodopa treatment alters both expression and function of D3 receptors in the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus
probenecid (
MPTP/p) mouse model of PD. drd3-EGFP reporter mice were injected biweekly with saline or
MPTP and
probenecid for a 5-week period. During the last two weeks of the 5-week period, the mice were administered saline or
levodopa twice daily. Locomotor activity was measured during the treatment period. D3 receptor expression was determined by western blot analysis. D3 receptor signaling function was determined at tissue and single cell level by measuring the activation of D3
receptor-mitogen activated
protein kinase (MAPK) pathway. The drd3-EGFP mice administered
MPTP/p exhibited akinesia/
bradykinesia. Expression of D3 receptor
protein in the dorsal striatum specifically increased in the
MPTP/p-treated mice administered
levodopa. In the dorsal striatum of
levodopa and
MPTP/p-treated drd3-EGFP mice, administration of a D3 receptor-selective dose of agonist,
PD128907, failed to activate D3 receptor-MAPK signaling. These results suggest that
MPTP-induced lesion and chronic
levodopa treatment alters D3 receptor expression and function in the dorsal striatum which could contribute to the development of
dyskinesias and other motor side-effects.