title: The NR2B-selective NMDA receptor antagonist CP-101,606 exacerbates L-DOPA-induced dyskinesia and provides mild potentiation of anti-parkinsonian effects of L-DOPA in the MPTP-lesioned marmoset model of Parkinson's disease.
abstract: In Parkinson's disease (PD), degeneration of the dopaminergic nigrostriatal pathway leads to enhanced transmission at NMDA receptors containing NR2B subunits. Previous studies have shown that some, but not all, NR2B-containing NMDA receptor antagonists alleviate parkinsonian symptoms in animal models of PD. Furthermore, enhanced NMDA receptor-mediated transmission underlies the generation of L-DOPA-induced dyskinesia (LID). The subunit content of NMDA receptors responsible for LID is not clear. Here, we assess the actions of the NMDA antagonist CP-101,606 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson's disease. CP-101,606 is selective for NMDA receptors containing NR2B subunits, with higher affinity for NR1/NR2B complexes compared to ternary NR1/NR2A/NR2B complexes. CP-101,606 had no significant effect on parkinsonian symptoms when administered as monotherapy over a range of doses (0.1-10 mg/kg). CP-101,606 provided a modest potentiation of the anti-parkinsonian actions of L-DOPA (8 mg/kg), although, at doses of 1 and 3 mg/kg, CP-101,606 exacerbated LID. Results of this study provide further evidence of differences in the anti-parkinsonian activity and effects on LID of the NR2B subunit selective NMDA receptor antagonists. These distinctions may reflect disparities in action on NR1/NR2B as opposed to NR1/NR2A/NR2B receptors.
authors.affiliation: Toronto Western Research Institute, ON, M5T 2S8 Canada. jnash@uhnres.utoronto.ca
authors.forename: J E
authors.initials: JE
authors.lastname: Nash
authors.forename: P
authors.initials: P
authors.lastname: Ravenscroft
authors.forename: S
authors.initials: S
authors.lastname: McGuire
authors.forename: A R
authors.initials: AR
authors.lastname: Crossman
authors.forename: F S
authors.initials: FS
authors.lastname: Menniti
authors.forename: J M
authors.initials: JM
authors.lastname: Brotchie
mesh_terms: D000818:Animals; D002144:Callithrix; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D005260:Female; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D016059:Range of Motion, Articular / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D017211:Treatment Failure
chemical_list: C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D007980:Levodopa; C095106:traxoprodil mesylate