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Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson's disease: role of NMDA vs. 5-HT1A receptors
Ist Teil von
The European journal of neuroscience, 2012-11, Vol.36 (9), p.3224-3234
Ort / Verlag
Oxford, UK: Blackwell Publishing Ltd
Erscheinungsjahr
2012
Link zum Volltext
Quelle
Wiley Online Library Journals Frontfile Complete
Beschreibungen/Notizen
Amantadine and dextromethorphan suppress levodopa (L‐DOPA)‐induced dyskinesia (LID) in patients with Parkinson’s disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6‐hydroxydopamine (6‐OHDA) rat model. These effects have been attributed to N‐methyl‐d‐aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5‐HT) uptake and cause 5‐HT overflow, leading to stimulation of 5‐HT1A receptors, which has been shown to reduce LID. We undertook a study in 6‐OHDA rats to determine whether the anti‐dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5‐HT1A agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae‐Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM‐suppressing effect of amantadine was not affected by the 5‐HT1A antagonist WAY‐100635, but was partially reversed by the NMDA agonist d‐cycloserine. Conversely, the AIM‐suppressing effect of dextromethorphan was prevented by WAY‐100635 but not by d‐cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L‐DOPA in sensorimotor tests. We conclude that the anti‐dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5‐HT1A agonism. Combined with previous work from our group, our results support the investigation of 5‐HT1A agonists as pharmacotherapies for LID in PD patients.
Dextromethorphan (DM) suppressed L‐DOPA‐induced AIMs. This effect was blocked by the 5‐HT1A antagonist WAY‐100635 (WAY), but not the NMDA agonist D‐cycloserine (DCS). *P < 0.05 relative to vehicle (Veh); #P < 0.01 relative to DM, +P < 0.001 relative to DCS.