title: L-745,870 reduces the expression of abnormal involuntary movements in the 6-OHDA-lesioned rat.
abstract: L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease, but chronic administration is complicated by the development of dyskinesia. We have previously demonstrated that the dopamine D4 receptor antagonist L-745,870 reduces the severity of L-DOPA-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque without compromising L-DOPA antiparkinsonian benefits. In the current study, we have addressed the effects of L-745,870 on the expression of L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine-lesioned rat. Rats were primed with repeated L-DOPA administration, after which acute challenges of L-DOPA/L-745,870 (vehicle, 0.1, 0.3 and 1 mg/kg) were administered, and AIMs were assessed. Rotarod performance and AIMs were assessed. In L-DOPA-primed rats, L-745,870 (1 mg/kg, but not lower doses) alleviated previously established AIMs (by 84%, P<0.001). Whereas rotarod performance was significantly improved by L-DOPA/vehicle treatment, L-DOPA/L-745,870 failed to improve rotarod performance (P>0.05), suggesting that, in contrast to the MPTP-lesioned macaque, L-745,870 reduces L-DOPA antiparkinsonian benefit in the rat model. Overall, these data suggest that L-745,870 may have a narrow therapeutic window as an antidyskinetic agent in advanced Parkinson's disease.
authors.affiliation: aToronto Western Research Institute bDivision of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Huot
authors.forename: Tom H
authors.initials: TH
authors.lastname: Johnston
authors.forename: James B
authors.initials: JB
authors.lastname: Koprich
authors.forename: Maria C
authors.initials: MC
authors.lastname: Espinosa
authors.forename: Maria Gabriela
authors.initials: MG
authors.lastname: Reyes
authors.forename: Susan H
authors.initials: SH
authors.lastname: Fox
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D007980:Levodopa / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D000978:Antiparkinson Agents; D018492:Dopamine Antagonists; D011725:Pyridines; D011758:Pyrroles; D007980:Levodopa; D016627:Oxidopamine