title: Dyskinesias do not develop after chronic intermittent levodopa therapy in clinically hemiparkinsonian rhesus monkeys.
abstract: The stable 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian (HP) rhesus monkey model of Parkinson's disease (PD) has been frequently used to test preclinical experimental therapeutics targeted to treat patients with advanced PD who suffer from motor fluctuations and drug-induced dyskinesias. We retrospectively analyzed data from 17 stable HP rhesus monkeys treated long-term with chronic intermittent dosing of levodopa (LD) in an attempt to induce choreoathetoid and dystonic dyskinesias. Rhesus monkeys in stable HP state for greater than 6 months as confirmed by multiple blinded behavioral ratings and (18)F-dopa Positron Emission Tomography (PET) were treated with optimal doses of LD to provide maximal amelioration of unilateral clinical parkinsonism without any adverse effects. Thereafter, each animal was given chronic intermittent daily challenge with doses of LD up to 700 mg/day orally or with 300 mg/kg/day parenteral injections. LD treatments failed to induce choreoathetoid and dystonic dyskinesias in these animals despite chronic intermittent high dose administration. These results suggest that the stable strictly unilateral HP rhesus monkey model of PD may not be a suitable animal model to test experimental therapeutics targeted against dyskinesias, and that bilateral parkinsonian rhesus models that readily demonstrate drug-induced dyskinesias and clinically relevant motor fluctuations are more appropriate for preclinical experimental testing of therapies designed to treat patients with advanced PD.
authors.affiliation: Department of Neurology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lieu
authors.forename: Milind
authors.initials: M
authors.lastname: Deogaonkar
authors.forename: Roy A E
authors.initials: RA
authors.lastname: Bakay
authors.forename: Thyagarajan
authors.initials: T
authors.lastname: Subramanian
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001522:Behavior, Animal; D002339:Carotid Arteries; D003216:Conditioning, Operant; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000473:pathology; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives; D015259:Dopamine Agents / Q000008:administration & dosage; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D004421:Dystonia / Q000150:complications; D005260:Female; D007275:Injections, Intravenous; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D020267:MPTP Poisoning / Q000150:complications* / Q000188:drug therapy*; D008253:Macaca mulatta; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy*; D011597:Psychomotor Performance; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000473:pathology
chemical_list: D000978:Antiparkinson Agents; D015259:Dopamine Agents; D019275:Radiopharmaceuticals; C043437:fluorodopa F 18; D007980:Levodopa; D004295:Dihydroxyphenylalanine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine