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

• DOI: 10.2147/cia.s41464
• Publication Date: 2013-03-26T00:02:33Z
• Authors: Zhenguo Liu; Na Wu; Lu Song; Guiyun Cui; Weien Yuan
• Keywords: 0301 basic medicine; Dyskinesia, Drug-Induced; Arrestins; Blotting, Western; L-DOPA; Down-Regulation; 6-hydroxydopamine; GRK6; Receptors, N-Methyl-D-Aspartate; Statistics, Nonparametric; Antiparkinson Agents; Levodopa; Rats, Sprague-Dawley; 03 medical and health sciences; 0302 clinical medicine; GPCR; AIM; Animals; LID; Original Research; Analysis of Variance; 0303 health sciences; Behavior, Animal; RC952-954.6; Parkinson Disease; G-Protein-Coupled Receptor Kinases; Corpus Striatum; Rats; 3. Good health; dyskinesia; Geriatrics; Clinical Interventions in Aging; dopamine; nigra

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.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.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.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.