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:
https://lup.lub.lu.se/record/1392232
- author
- Rylander, Daniella
LU
; Recchia, Alessandra
LU
; Mela, Flora
LU
; Dekundy, Andrzej
; Danysz, Wojciech
and Cenci Nilsson, Angela
LU
- organization
- publishing date
- 2009
- 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
- 2016-04-01 13:55:36
- date last changed
- 2022-04-06 07:56:04
@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}},
doi = {{10.1124/jpet.108.150425}},
volume = {{330}},
year = {{2009}},
}