The predictive validity of the drug-naive bilaterally MPTP-treated monkey as a model of Parkinson's disease: effects of L-DOPA and the D1 agonist SKF 82958.
The aim of this study was twofold: (1) to study the predictive validity of the drug-naive, bilaterally MPTP-treated monkey as an animal model of Parkinson's disease (PD), and (2) to investigate the therapeutic and undesired effects of the D1 agonist SKF 82958 as compared to L-DOPA treatment, in drug-naive and L-DOPA pretreated monkeys. A detailed ethogram was used, allowing the separation of therapeutic and undesired effects. Eight weeks after bilateral intracarotid MPTP administration, SKF 82958 (1 mg/kg, n = 4, SKF 82958, naive group) or methyl-L-DOPA + carbi-dopa (10 + 2.5 mg/kg, n = 4, L-DOPA group) was administered intramuscularly for 22 days. After a drug-free period of eight weeks, the L-DOPA group was treated with SKF 82958 for 22 days (SKF 82959, 1 mg/kg, n=4, pretreated). All drug treatments increased the parameters used classically to evaluate dopaminergic drugs, namely body displacement, dyskinesia and dystonia. However, the new detailed analysis revealed that L-DOPA, but not SKF 82958, had therapeutic effects, reflected by an increase in goal-directed fore-limb use. SKF 82958, but not L-DOPA, induced additional undesired effects; including epileptoid behaviours in both drug-naive and drug-pretreated monkeys. In one L-DOPA-unresponsive monkey, SKF 82958 did induce minor therapeutic effects, as well as undesired effects. Although the effects of SKF 82958 on fore-limb movements, rotational behaviours and body displacement were comparable in the naive and pretreated group, SKF 82958 re-initiated undesired effects in the L-DOPA pretreated group from day one. It is concluded that the bilaterally MPTP-treated monkey is an animal model with predictive validity for PD: it adequately predicts the therapeutic effects and undesired effects of L-DOPA. Furthermore, it is concluded that SKF 82958 is less effective than L-DOPA in the treatment of PD, because it did not induce therapeutic effects, but instead elicited several undesired effects.
Andringa
G
G
Research Institute of Neuroscience, Department of Neurology, Vrije Universiteit of Amsterdam, The Netherlands.
Lubbers
L
L
Drukarch
B
B
Stoof
J C
JC
Cools
A R
AR
D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001132:Arm / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000627:therapeutic use*; D015259:Dopamine Agents / Q000633:toxicity*; D018491:Dopamine Agonists / Q000627:therapeutic use*; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000523:psychology; D004421:Dystonia / Q000188:drug therapy / Q000523:psychology; D004569:Electroencephalography / Q000187:drug effects; D004827:Epilepsy / Q000523:psychology; D007980:Levodopa / Q000627:therapeutic use*; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000523:psychology*; D008253:Macaca mulatta; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009068:Movement / Q000187:drug effects; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000188:drug therapy* / Q000523:psychology; D011237:Predictive Value of Tests; D017447:Receptors, Dopamine D1 / Q000819:agonists*
D000978:Antiparkinson Agents; D001552:Benzazepines; D015259:Dopamine Agents; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D007980:Levodopa; C071262:SK&F 82958