Distinct changes in cAMP and extracellular signal-regulated protein kinase signalling in L-DOPA-induced dyskinesia.
PLoS ONE. 2010-08-23; 5(8): e12322
DOI: 10.1371/journal.pone.0012322
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1. PLoS One. 2010 Aug 23;5(8):e12322. doi: 10.1371/journal.pone.0012322.
Distinct changes in cAMP and extracellular signal-regulated protein kinase
signalling in L-DOPA-induced dyskinesia.
Santini E(1), Sgambato-Faure V, Li Q, Savasta M, Dovero S, Fisone G, Bezard E.
Author information:
(1)Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
BACKGROUND: In rodents, the development of dyskinesia produced by L-DOPA in the
dopamine-depleted striatum occurs in response to increased dopamine D1
receptor-mediated activation of the cAMP – protein kinase A and of the
Ras-extracellular signal-regulated kinase (ERK) signalling pathways. However,
very little is known, in non-human primates, about the regulation of these
signalling cascades and their association with the induction, manifestation
and/or maintenance of dyskinesia.
METHODOLOGY/RESULTS: We here studied, in the gold-standard non-human primate
model of Parkinson’s disease, the changes in PKA-dependent phosphorylation of
DARPP-32 and GluR1 AMPA receptor, as well as in ERK and ribosomal protein S6 (S6)
phosphorylation, associated to acute and chronic administration of L-DOPA.
Increased phosphorylation of DARPP-32 and GluR1 was observed in both L-DOPA
first-ever exposed and chronically-treated dyskinetic parkinsonian monkeys. In
contrast, phosphorylation of ERK and S6 was enhanced preferentially after acute
L-DOPA administration and decreased during the course of chronic treatment.
CONCLUSION: Dysregulation of cAMP signalling is maintained during the course of
chronic L-DOPA administration, while abnormal ERK signalling peaks during the
initial phase of L-DOPA treatment and decreases following prolonged exposure.
While cAMP signalling enhancement is associated with dyskinesia, abnormal ERK
signalling is associated with priming.
DOI: 10.1371/journal.pone.0012322
PMCID: PMC2925943
PMID: 20808799 [Indexed for MEDLINE]