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Pharmacological Modulation of Glutamate Transmission in a Rat Model of l-DOPA-Induced Dyskinesia: Effects on Motor Behavior and Striatal Nuclear SignalingS⃞
- Publication Year :
- 2009
- Publisher :
- American Society for Pharmacology and Experimental Therapeutics, 2009.
-
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 signaling 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 (mGluR), (2-methyl-1,3-thiazol-4-yl) ethynylpyridine (MTEP) for mGluR5 and (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methane sulfonate (EMQMCM) for mGluR1; an agonist of group II mGluR, 1R,4R,5S,6R-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268); N-methyl-d-aspartate (NMDA)-R2B subunit (NR2B)-selective NMDA receptor antagonists 1-[2-(4-hydroxyphenoxy)ethyl]-4-[(4-methylphenyl)methyl]-4-piperidinol hydrochloride (Ro631908) and (±)-(R*,S*)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)1-piperidine propanol (Ro256981); and an L-type calcium channel antagonist, 4-(4-benzofurazanyl)-1,-4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester (isradipine). Dyskinesia and rotarod performance were monitored during chronic drug treatment. The striatal expression of phospho-extracellular signal-regulated kinase (ERK) 1/2 and mitogen- and stress-activated kinase (MSK)-1, or prodynorphin mRNA was examined after acute or chronic treatment, respectively. In the acute treatment studies, only MTEP and EMQMCM significantly attenuated l-DOPA-induced phospho-ERK1/2 and/or phospho-MSK-1 expression, with 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 antiakinetic effects but did not reduce dyskinesia. Only MTEP blocked the up-regulation of prodynorphin mRNA induced by l-DOPA. Among the pharmacological treatments 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.
- Subjects :
- Dyskinesia, Drug-Induced
Glutamic Acid
Biology
Pharmacology
Motor Activity
Receptors, Metabotropic Glutamate
Synaptic Transmission
Levodopa
Rats, Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
Neuropharmacology
medicine
Excitatory Amino Acid Agonists
Animals
030304 developmental biology
0303 health sciences
Metabotropic glutamate receptor 5
Glutamate receptor
Methane sulfonate
Corpus Striatum
3. Good health
Rats
Disease Models, Animal
MTEP
Dyskinesia
Metabotropic glutamate receptor
Molecular Medicine
NMDA receptor
Metabotropic glutamate receptor 1
Female
medicine.symptom
Excitatory Amino Acid Antagonists
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....0a813b2feb5dd1feddf623ba4773b51d