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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/166566
- author
- Mela, Flora
; Marti, Matteo
; Dekundy, Andrzej
; Danysz, Wojciech
; Morari, Michele
and Cenci Nilsson, Angela
LU
- organization
- publishing date
- 2007
- 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
- pmid:17359492
- 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
- 2016-04-01 15:27:19
- date last changed
- 2022-04-06 23:08:15
@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}},
keywords = {{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}},
doi = {{10.1111/j.1471-4159.2007.04456.x}},
volume = {{101}},
year = {{2007}},
}