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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.
J Neurochem. 2007 Apr; 101(2):483-97.JN

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.

Authors+Show Affiliations

Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17359492

Citation

Mela, Flora, et al. "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." Journal of Neurochemistry, vol. 101, no. 2, 2007, pp. 483-97.
Mela F, Marti M, Dekundy A, et al. 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. J Neurochem. 2007;101(2):483-97.
Mela, F., Marti, M., Dekundy, A., Danysz, W., Morari, M., & Cenci, M. A. (2007). 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. Journal of Neurochemistry, 101(2), 483-97.
Mela F, et al. 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. J Neurochem. 2007;101(2):483-97. PubMed PMID: 17359492.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Mela,Flora, AU - Marti,Matteo, AU - Dekundy,Andrzej, AU - Danysz,Wojciech, AU - Morari,Michele, AU - Cenci,M Angela, Y1 - 2007/01/15/ PY - 2007/3/16/pubmed PY - 2007/6/2/medline PY - 2007/3/16/entrez SP - 483 EP - 97 JF - Journal of neurochemistry JO - J Neurochem VL - 101 IS - 2 N2 - 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. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/17359492/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_ L2 - https://doi.org/10.1111/j.1471-4159.2007.04456.x DB - PRIME DP - Unbound Medicine ER -