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Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors

Westin, Jenny LU ; Vercammen, Linda; Strome, Elissa LU ; Konradi, Christine and Cenci Nilsson, Angela LU (2007) In Biological Psychiatry 62(7). p.800-810
Abstract
Background: We examined the activation pattern of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and its dependence on D1 versus D2 dopamine receptors in hemiparkinsonian rats treated with 3,4-dihydroxyphenyl-L-alanine (L-DOPA). Methods: 6-Hydroxydopamine-lesioned rats were treated acutely or chronically with L-DOPA in combination with antagonists for D1 or D2 receptors. Development of dyskinesia was monitored in animals receiving chronic drug treatment. Phosphorylation of ERK1/2, mitogen- and stress-activated protein kinase-1 (MSK-1), and the levels of FosB/Delta FosB expression were examined immunohistochemically. Results: L-DOPA treatment caused phosphorylation of ERK1/2 in the dopamine-denervated striatum after acute and... (More)
Background: We examined the activation pattern of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and its dependence on D1 versus D2 dopamine receptors in hemiparkinsonian rats treated with 3,4-dihydroxyphenyl-L-alanine (L-DOPA). Methods: 6-Hydroxydopamine-lesioned rats were treated acutely or chronically with L-DOPA in combination with antagonists for D1 or D2 receptors. Development of dyskinesia was monitored in animals receiving chronic drug treatment. Phosphorylation of ERK1/2, mitogen- and stress-activated protein kinase-1 (MSK-1), and the levels of FosB/Delta FosB expression were examined immunohistochemically. Results: L-DOPA treatment caused phosphorylation of ERK1/2 in the dopamine-denervated striatum after acute and chronic administration. Similar levels were observed in matrix and striosomes, and in enkephalin-positive and dynorphin-positive neurons. The severity of dyskinesia was positively correlated with phospho-ERK1/2 levels. Phosphorylation of ERK1/2 and MSK-1 was dose-dependently blocked by SCH23390, but not by raclopride. SCH23390 also inhibited the development of dyskinesia and the induction of FosB/Delta FosB. Conclusions: L-DOPA produces pronounced activation of ERK1/2 signaling in the dopamine-denervated striatum through a D1-receptor-dependent mechanism. This effect is associated with the development of dyskinesia. Phosphorylated ERK1/2 is localized to both dynorphinergic and enkephalinergic striatal neurons, suggesting a general role of ERK1/2 as a plasticity molecule during L-DOPA treatment. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
signaling pathways, therapy, rodent, Parkinson's disease, gene transcription, motor complications
in
Biological Psychiatry
volume
62
issue
7
pages
800 - 810
publisher
Society of Biological Psychiatry Published by Elsevier Inc.
external identifiers
  • wos:000249511500012
  • scopus:34047178328
ISSN
0006-3223
DOI
10.1016/j.biopsych.2006.11.032
language
English
LU publication?
yes
id
aa4aaa66-db25-4ca8-aa2d-1505adea3382 (old id 688415)
date added to LUP
2007-12-19 11:14:27
date last changed
2017-10-22 03:45:10
@article{aa4aaa66-db25-4ca8-aa2d-1505adea3382,
  abstract     = {Background: We examined the activation pattern of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and its dependence on D1 versus D2 dopamine receptors in hemiparkinsonian rats treated with 3,4-dihydroxyphenyl-L-alanine (L-DOPA). Methods: 6-Hydroxydopamine-lesioned rats were treated acutely or chronically with L-DOPA in combination with antagonists for D1 or D2 receptors. Development of dyskinesia was monitored in animals receiving chronic drug treatment. Phosphorylation of ERK1/2, mitogen- and stress-activated protein kinase-1 (MSK-1), and the levels of FosB/Delta FosB expression were examined immunohistochemically. Results: L-DOPA treatment caused phosphorylation of ERK1/2 in the dopamine-denervated striatum after acute and chronic administration. Similar levels were observed in matrix and striosomes, and in enkephalin-positive and dynorphin-positive neurons. The severity of dyskinesia was positively correlated with phospho-ERK1/2 levels. Phosphorylation of ERK1/2 and MSK-1 was dose-dependently blocked by SCH23390, but not by raclopride. SCH23390 also inhibited the development of dyskinesia and the induction of FosB/Delta FosB. Conclusions: L-DOPA produces pronounced activation of ERK1/2 signaling in the dopamine-denervated striatum through a D1-receptor-dependent mechanism. This effect is associated with the development of dyskinesia. Phosphorylated ERK1/2 is localized to both dynorphinergic and enkephalinergic striatal neurons, suggesting a general role of ERK1/2 as a plasticity molecule during L-DOPA treatment.},
  author       = {Westin, Jenny and Vercammen, Linda and Strome, Elissa and Konradi, Christine and Cenci Nilsson, Angela},
  issn         = {0006-3223},
  keyword      = {signaling pathways,therapy,rodent,Parkinson's disease,gene transcription,motor complications},
  language     = {eng},
  number       = {7},
  pages        = {800--810},
  publisher    = {Society of Biological Psychiatry Published by Elsevier Inc.},
  series       = {Biological Psychiatry},
  title        = {Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors},
  url          = {http://dx.doi.org/10.1016/j.biopsych.2006.11.032},
  volume       = {62},
  year         = {2007},
}