Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson's disease: Role of NMDA vs. 5-HT1A receptors

Melanie A. Paquette, Alex A. Martinez, Teresa Macheda, Charles K. Meshul, Steven W. Johnson, S. Paul Berger, Andrea Giuffrida

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3224-3234
Number of pages11
JournalEuropean Journal of Neuroscience
Volume36
Issue number9
DOIs
StatePublished - Nov 1 2012

Keywords

  • 6-hydroxydopamine
  • Dyskinesia
  • L-DOPA
  • Parkinson's disease
  • Serotonin

ASJC Scopus subject areas

  • Neuroscience(all)

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