Advanced

Pharmacological modulation of glutamate transmission in a rat model of L-DOPA-induced dyskinesia: effects on motor behavior and striatal nuclear signalling.

Rylander, Daniella LU ; Recchia, Alessandra LU ; Mela, Flora LU ; Dekundy, Andrzej; Danysz, Wojciech and Cenci Nilsson, Angela LU (2009) In Journal of Pharmacology and Experimental Therapeutics 330(1). p.227-235
Abstract
L-DOPA-induced dyskinesia (LID) in Parkinson's disease has been linked to altered dopamine and glutamate transmission within the basal ganglia. In the present study, we compared compounds targeting specific subtypes of glutamate receptors or calcium channels for their ability to attenuate LID and the associated activation of striatal nuclear signalling and gene expression in the rat. Rats with 6-hydroxydopamine lesions were treated acutely or chronically with L-DOPA in combination with the following selective compounds: antagonists of group I metabotropic glutamate receptors (MTEP for mGluR5, and EMQMCM for mGluR1), agonist of group II mGluR (LY379268), NR2B-selective NMDA receptor antagonists (Ro631908 and Ro256981), and antagonist of... (More)
L-DOPA-induced dyskinesia (LID) in Parkinson's disease has been linked to altered dopamine and glutamate transmission within the basal ganglia. In the present study, we compared compounds targeting specific subtypes of glutamate receptors or calcium channels for their ability to attenuate LID and the associated activation of striatal nuclear signalling and gene expression in the rat. Rats with 6-hydroxydopamine lesions were treated acutely or chronically with L-DOPA in combination with the following selective compounds: antagonists of group I metabotropic glutamate receptors (MTEP for mGluR5, and EMQMCM for mGluR1), agonist of group II mGluR (LY379268), NR2B-selective NMDA receptor antagonists (Ro631908 and Ro256981), and antagonist of L-type calcium channels (isradipine). Dyskinesia and rotarod performance were monitored during chronic drug treatment. The striatal expression of phospho-ERK1/2 and MSK-1, or prodynorphin mRNA were examined following acute or chronic treatment, respectively. In the acute treatment studies, only MTEP and EMQMCM significantly attenuated L-DOPA-induced phospho-ERK 1/2 and/or phospho-MSK-1 expression, MTEP being the most effective (70-80% reduction). In the chronic experiment, only MTEP significantly attenuated dyskinesia without adverse motor effects, whereas EMQMCM and LY379268 inhibited the L-DOPA-induced improvement in rotarod performance. The NR2B antagonist had positive anti-akinetic effects but did not reduce dyskinesia. Only MTEP blocked the upregulation of prodynorphin mRNA induced by L-DOPA. Among the pharmacological treatments here examined, MTEP was most effective in inhibiting LID and the associated molecular alterations. Antagonism of mGluR5 seems to be a promising strategy to reduce dyskinesia in Parkinson's disease. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Pharmacology and Experimental Therapeutics
volume
330
issue
1
pages
227 - 235
publisher
American Society for Pharmacology and Experimental Therapeutics
external identifiers
  • wos:000267280300026
  • pmid:19357321
  • scopus:67649847847
ISSN
1521-0103
DOI
10.1124/jpet.108.150425
language
English
LU publication?
yes
id
6d6ad786-1d1b-47e1-abe0-274452e7465b (old id 1392232)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19357321?dopt=Abstract
date added to LUP
2009-05-06 14:24:04
date last changed
2017-11-05 04:03:49
@article{6d6ad786-1d1b-47e1-abe0-274452e7465b,
  abstract     = {L-DOPA-induced dyskinesia (LID) in Parkinson's disease has been linked to altered dopamine and glutamate transmission within the basal ganglia. In the present study, we compared compounds targeting specific subtypes of glutamate receptors or calcium channels for their ability to attenuate LID and the associated activation of striatal nuclear signalling and gene expression in the rat. Rats with 6-hydroxydopamine lesions were treated acutely or chronically with L-DOPA in combination with the following selective compounds: antagonists of group I metabotropic glutamate receptors (MTEP for mGluR5, and EMQMCM for mGluR1), agonist of group II mGluR (LY379268), NR2B-selective NMDA receptor antagonists (Ro631908 and Ro256981), and antagonist of L-type calcium channels (isradipine). Dyskinesia and rotarod performance were monitored during chronic drug treatment. The striatal expression of phospho-ERK1/2 and MSK-1, or prodynorphin mRNA were examined following acute or chronic treatment, respectively. In the acute treatment studies, only MTEP and EMQMCM significantly attenuated L-DOPA-induced phospho-ERK 1/2 and/or phospho-MSK-1 expression, MTEP being the most effective (70-80% reduction). In the chronic experiment, only MTEP significantly attenuated dyskinesia without adverse motor effects, whereas EMQMCM and LY379268 inhibited the L-DOPA-induced improvement in rotarod performance. The NR2B antagonist had positive anti-akinetic effects but did not reduce dyskinesia. Only MTEP blocked the upregulation of prodynorphin mRNA induced by L-DOPA. Among the pharmacological treatments here examined, MTEP was most effective in inhibiting LID and the associated molecular alterations. Antagonism of mGluR5 seems to be a promising strategy to reduce dyskinesia in Parkinson's disease.},
  author       = {Rylander, Daniella and Recchia, Alessandra and Mela, Flora and Dekundy, Andrzej and Danysz, Wojciech and Cenci Nilsson, Angela},
  issn         = {1521-0103},
  language     = {eng},
  number       = {1},
  pages        = {227--235},
  publisher    = {American Society for Pharmacology and Experimental Therapeutics},
  series       = {Journal of Pharmacology and Experimental Therapeutics},
  title        = {Pharmacological modulation of glutamate transmission in a rat model of L-DOPA-induced dyskinesia: effects on motor behavior and striatal nuclear signalling.},
  url          = {http://dx.doi.org/10.1124/jpet.108.150425},
  volume       = {330},
  year         = {2009},
}