Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson%26apos;s disease: role of NMDA vs. 5-HT1A receptors

作者：Paquette Melanie A^*; Martinez Alex A; Macheda Teresa; Meshul Charles K; Johnson Steven W; Berger S Paul; Giuffrida Andrea

来源：European Journal of Neuroscience, 2012, 36(9): 3224-3234.

DOI：10.1111/j.1460-9568.2012.08243.x

• 6-hydroxydopamine
• dyskinesia
• L-DOPA
• Parkinson%26apos
• s disease
• serotonin

Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinsons 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.

• 出版日期2012-11