Distinct changes in cAMP and extracellular signal-regulated protein kinase signalling in L-DOPA-induced dyskinesia.

Abstract

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.

• Authors: Emanuela Santini, Veronique Sgambato-Faure, Qin Li, Marc Savasta, Sandra Dovero, Gilberto Fisone, Erwan Bezard
• Journal: PloS one (PLoS One) Vol. 5 Issue 8 Pg. e12322 (Aug 23 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 20808799 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dopamine and cAMP-Regulated Phosphoprotein 32
• Levodopa
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases
• Extracellular Signal-Regulated MAP Kinases
• ras Proteins

Topics

• Animals
• Cyclic AMP (metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Dopamine and cAMP-Regulated Phosphoprotein 32 (metabolism)
• Dyskinesias (etiology, metabolism, pathology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Levodopa (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Macaca mulatta
• Parkinsonian Disorders (chemically induced, metabolism, pathology)
• ras Proteins (metabolism)