title: Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson's disease: role of NMDA vs. 5-HT1A receptors.
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-HT(1A)  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-HT(1A)  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-HT(1A)  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-HT(1A)  agonism. Combined with previous work from our group, our results support the investigation of 5-HT(1A)  agonists as pharmacotherapies for LID in PD patients.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, USA. paquettem@lilly.com
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Paquette
authors.forename: Alex A
authors.initials: AA
authors.lastname: Martinez
authors.forename: Teresa
authors.initials: T
authors.lastname: Macheda
authors.forename: Charles K
authors.initials: CK
authors.lastname: Meshul
authors.forename: Steven W
authors.initials: SW
authors.lastname: Johnson
authors.forename: S Paul
authors.initials: SP
authors.lastname: Berger
authors.forename: Andrea
authors.initials: A
authors.lastname: Giuffrida
mesh_terms: D000547:Amantadine / Q000627:therapeutic use*; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D003523:Cycloserine / Q000494:pharmacology; D003915:Dextromethorphan / Q000627:therapeutic use*; D015259:Dopamine Agents / Q000627:therapeutic use*; D020820:Dyskinesias / Q000188:drug therapy* / Q000503:physiopathology; D007980:Levodopa / Q000627:therapeutic use; D008297:Male; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000627:therapeutic use; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000627:therapeutic use
chemical_list: D000978:Antiparkinson Agents; D015259:Dopamine Agents; D010879:Piperazines; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D007980:Levodopa; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D003915:Dextromethorphan; D016627:Oxidopamine; D003523:Cycloserine; D000547:Amantadine