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Effect of memantine on L-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease
- Source :
- Neuroscience. 265
- Publication Year :
- 2013
-
Abstract
- An increasing body of experimental evidence demonstrates that the glutamatergic system is involved in the genesis of l-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID). Indeed, the N-methyl-d-aspartate (NMDA) receptor antagonist amantadine is the only anti-dyskinetic compound used in patients, albeit with limited efficacy and side effects. In this study, we investigated the anti-dyskinetic properties of memantine, a non-competitive NMDA receptor antagonist in clinical use for the treatment of dementia, in the 6-hydroxy-dopamine (6-OHDA)-lesion rat model of Parkinson's disease. For comparison, parallel experiments were also performed with amantadine. First, we investigated the acute effect of different doses of memantine (5, 10, 15 and 20mg/kg), and amantadine (10, 20, 40, 60mg/kg) on established dyskinesia induced by L-DOPA (6mg/kg plus benserazide). Results showed that both memantine and amantadine produced a significant reduction of LID. Afterward, drug-naive and L-DOPA-primed 6-OHDA-lesioned rats were sub-chronically treated with daily injections of L-DOPA (6mg/kg plus benserazide) alone, or in combination with the effective doses of memantine, while amantadine was tested in already dyskinetic rats. Results showed that memantine significantly dampened dyskinesia in both drug-naive and L-DOPA-primed rats, but only during the first few days of administration. In fact, the anti-dyskinetic effect of memantine was completely lost already at the fifth administration, indicating a rapid induction of tolerance. Interestingly, a 3-week washout period was not sufficient to restore the anti-dyskinetic effect of the drug. Similarly, amantadine was able to dampen already established dyskinesia only during the first day of administration. Moreover, memantine partially decreased the therapeutic effect of L-DOPA, as showed by the result of the stepping test. Finally, loss of the anti-dyskinetic effect of memantine was associated to increased synaptic GluN2A/GluN2B ratio at striatal synaptic membranes. Our results are in line with clinical observations suggesting that NMDA receptor blockade may only be transiently effective against LID in PD patients.
- Subjects :
- Male
Parkinson's disease
medicine.drug_class
Pharmacology
Antiparkinson Agents
Levodopa
Rats, Sprague-Dawley
Dopamine
Memantine
medicine
Amantadine
Animals
Parkinson Disease, Secondary
Oxidopamine
Benserazide
Dyskinesias
business.industry
General Neuroscience
medicine.disease
Receptor antagonist
Rats
Disease Models, Animal
Dyskinesia
NMDA receptor
medicine.symptom
business
Excitatory Amino Acid Antagonists
medicine.drug
Subjects
Details
- ISSN :
- 18737544
- Volume :
- 265
- Database :
- OpenAIRE
- Journal :
- Neuroscience
- Accession number :
- edsair.doi.dedup.....005a8bfeaac79aa9023d27e5c70d2e8d