NMDA receptor regulation of levodopa-induced behavior and changes in striatal G protein-coupled receptor kinase 6 and â-arrestin-1 expression in parkinsonian rats

BACKGROUND Parkinson's disease is a neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra. The dopamine precursor, levodopa, remains the most effective and common treatment for this disorder. However, long-term administration of levodopa is known to induce characteristic dyskinesia, and molecular mechanisms underlying dyskinesia are poorly understood. METHODS In this study, we investigated the effect of 6-hydroxydopamine lesions in dopaminergic neurons and chronic treatment with levodopa on expression of G protein-coupled receptor kinase 6 and β-arrestin-1, two key regulators of G protein-coupled receptors, in the rat striatum. RESULTS We found that a unilateral 6-hydroxydopamine lesion reduced expression of G protein-coupled receptor kinase 6 and β-arrestin-1 protein in the lesioned striatum. Reduction of these two proteins persisted in 6-hydroxydopamine-lesioned rats on chronic levodopa treatment for 23 days. In addition, coadministration of the N-methyl-D-aspartate receptor antagonist, MK-801, and levodopa reversed the reduction of G protein-coupled receptor kinase 6 and β-arrestin-1 in the striatum. MK-801 also attenuated levodopa-induced dyskinetic behavior. CONCLUSION These data indicate that G protein-coupled receptor kinase 6 and β-arrestin-1 in striatal neurons are sensitive to dopamine depletion and are downregulated in rats with Parkinson's disease and in levodopa-treated rats with the disease. This downregulation seems to require activation of N-methyl-D-aspartate glutamate receptors.