title: NMDA receptor regulation of levodopa-induced behavior and changes in striatal G protein-coupled receptor kinase 6 and β-arrestin-1 expression in parkinsonian rats.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Na
authors.initials: N
authors.lastname: Wu
authors.forename: Lu
authors.initials: L
authors.lastname: Song
authors.forename: Xinxin
authors.initials: X
authors.lastname: Yang
authors.forename: Weien
authors.initials: W
authors.lastname: Yuan
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000494:pharmacology; D019390:Arrestins / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation; D004409:Dyskinesia, Drug-Induced; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism*; D007980:Levodopa / Q000009:adverse effects* / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D018709:Statistics, Nonparametric
chemical_list: D000978:Antiparkinson Agents; D019390:Arrestins; D016194:Receptors, N-Methyl-D-Aspartate; D007980:Levodopa; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6
keywords: G protein-coupled receptor kinase dyskinesia; G protein-coupled receptors; dopamine; levodopa; levodopa-induced dyskinesias