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Antagonism of metabotropic glutamate receptor type 5 attenuates l-DOPA-induced dyskinesia and its molecular and neurochemical correlates in a rat model of Parkinson's disease.

Mela, Flora; Marti, Matteo; Dekundy, Andrzej; Danysz, Wojciech; Morari, Michele and Cenci Nilsson, Angela LU (2007) In Journal of Neurochemistry 101(2). p.483-497
Abstract
Metabotropic glutamate receptor type 5 (mGluR5) modulates dopamine and glutamate neurotransmission at central synapses. In this study, we addressed the role of mGluR5 in L-DOPA-induced dyskinesia, a movement disorder that is due to abnormal activation of both dopamine and glutamate receptors in the basal ganglia. A selective and potent mGluR5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl] pyridine, was tested for its ability to modulate molecular, behavioural and neurochemical correlates of dyskinesia in 6-hydroxydopamine-lesioned rats treated with L-DOPA. The compound significantly attenuated the induction of abnormal involuntary movements (AIMs) by chronic L-DOPA treatment at doses that did not interfere with the rat physiological... (More)
Metabotropic glutamate receptor type 5 (mGluR5) modulates dopamine and glutamate neurotransmission at central synapses. In this study, we addressed the role of mGluR5 in L-DOPA-induced dyskinesia, a movement disorder that is due to abnormal activation of both dopamine and glutamate receptors in the basal ganglia. A selective and potent mGluR5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl] pyridine, was tested for its ability to modulate molecular, behavioural and neurochemical correlates of dyskinesia in 6-hydroxydopamine-lesioned rats treated with L-DOPA. The compound significantly attenuated the induction of abnormal involuntary movements (AIMs) by chronic L-DOPA treatment at doses that did not interfere with the rat physiological motor activities. These effects were paralleled by an attenuation of molecular changes that are strongly associated with the dyskinesiogenic action of L-DOPA (i.e. up-regulation of prodynorphin mRNA in striatal neurons). Using in vivo microdialysis, we found a temporal correlation between the expression of L-DOPA-induced AIMs and an increased GABA outflow within the substantia nigra pars reticulata. When co-administered with L-DOPA, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl] pyridine greatly attenuated both the increase in nigral GABA levels and the expression of AIMs. These data demonstrate that mGluR5 antagonism produces strong anti-dyskinetic effects in an animal model of Parkinson's disease through central inhibition of the molecular and neurochemical underpinnings of L-DOPA-induced dyskinesia. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
dynorphin, 3-[(2-methyl-1, 3-thiazol-4-yl)ethynyl]pyridine, enkephalin., GABA, L-DOPA-induced dyskinesia, metabotropic glutamate receptor 5
in
Journal of Neurochemistry
volume
101
issue
2
pages
483 - 497
publisher
Wiley-Blackwell
external identifiers
  • wos:000245312800017
  • scopus:34047186385
ISSN
1471-4159
DOI
10.1111/j.1471-4159.2007.04456.x
language
English
LU publication?
yes
id
c69a960d-9f45-42ba-81e7-dd4f78cd226f (old id 166566)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17359492&dopt=Abstract
date added to LUP
2007-07-18 10:37:06
date last changed
2017-09-10 04:24:28
@article{c69a960d-9f45-42ba-81e7-dd4f78cd226f,
  abstract     = {Metabotropic glutamate receptor type 5 (mGluR5) modulates dopamine and glutamate neurotransmission at central synapses. In this study, we addressed the role of mGluR5 in L-DOPA-induced dyskinesia, a movement disorder that is due to abnormal activation of both dopamine and glutamate receptors in the basal ganglia. A selective and potent mGluR5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl] pyridine, was tested for its ability to modulate molecular, behavioural and neurochemical correlates of dyskinesia in 6-hydroxydopamine-lesioned rats treated with L-DOPA. The compound significantly attenuated the induction of abnormal involuntary movements (AIMs) by chronic L-DOPA treatment at doses that did not interfere with the rat physiological motor activities. These effects were paralleled by an attenuation of molecular changes that are strongly associated with the dyskinesiogenic action of L-DOPA (i.e. up-regulation of prodynorphin mRNA in striatal neurons). Using in vivo microdialysis, we found a temporal correlation between the expression of L-DOPA-induced AIMs and an increased GABA outflow within the substantia nigra pars reticulata. When co-administered with L-DOPA, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl] pyridine greatly attenuated both the increase in nigral GABA levels and the expression of AIMs. These data demonstrate that mGluR5 antagonism produces strong anti-dyskinetic effects in an animal model of Parkinson's disease through central inhibition of the molecular and neurochemical underpinnings of L-DOPA-induced dyskinesia.},
  author       = {Mela, Flora and Marti, Matteo and Dekundy, Andrzej and Danysz, Wojciech and Morari, Michele and Cenci Nilsson, Angela},
  issn         = {1471-4159},
  keyword      = {dynorphin,3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine,enkephalin.,GABA,L-DOPA-induced dyskinesia,metabotropic glutamate receptor 5},
  language     = {eng},
  number       = {2},
  pages        = {483--497},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Neurochemistry},
  title        = {Antagonism of metabotropic glutamate receptor type 5 attenuates l-DOPA-induced dyskinesia and its molecular and neurochemical correlates in a rat model of Parkinson's disease.},
  url          = {http://dx.doi.org/10.1111/j.1471-4159.2007.04456.x},
  volume       = {101},
  year         = {2007},
}