title: L-DOPA-induced behavioral sensitization of motor activity in the MPTP-treated common marmoset as a Parkinson's disease model.
abstract: l-DOPA is the gold standard for treatment of Parkinson's disease (PD). However, the drug produces some serious side effects, including dyskinesia, which is characterized by repetitive involuntary movements-including chorea. In the present preclinical study using a nonhuman primate model, dyskinesia caused by repeated l-DOPA administration was investigated in the context of behavioral sensitization by objectively quantifying motor activity in the common marmoset of PD model (the Parkinsonian marmoset). Twelve male Parkinsonian marmosets previously treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and six intact male marmosets were used. The motor activity of each marmoset was measured using infrared sensors attached to each individual living cage. Parkinsonian marmosets (n=6) exhibited behavioral sensitization (enhanced motor activity) in 10weeks upon oral administration of l-DOPA (10mg/kg per day on 3days/week). These animals also exhibited dyskinesia characterized by repetitive rapid movements including chorea in 6-10weeks. Neither behavioral sensitization nor dyskinesia was observed in Parkinsonian marmosets given vehicle and in intact marmosets given l-DOPA at the same dose (both n=6 each). Behavioral sensitization was detected sensitively and objectively on motor activity only in Parkinsonian marmosets given repeated l-DOPA at a similar dose used in PD patients. The behavioral feature of the marmosets was dyskinesia similar to that of PD patients but appeared earlier than would be manifested in humans. In spite of statistically significant behavioral sensitization, some marmosets did not exhibit dyskinesia in the present limited l-DOPA administration period. Although both commonalities and differences may exist between behavioral sensitization and dyskinesia, behavioral sensitization is considered to be an objective, quantitative, sensitive and predictive measure of behavioral mechanism underlying dyskinesia in preclinical studies in evaluating compounds.
authors.affiliation: Central Institute for Experimental Animals, Kawasaki 210-0821, Japan. Electronic address: ando@ciea.or.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
authors.affiliation: Central Institute for Experimental Animals, Kawasaki 210-0821, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Central Institute for Experimental Animals, Kawasaki 210-0821, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Itoh
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002144:Callithrix; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology / Q000523:psychology*; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology*; D011897:Random Allocation
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
keywords: Behavioral sensitization; Common marmoset; Dyskinesia; MPTP; Monkey; Motor activity; Parkinson's disease; l-DOPA