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 SKF82958

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 Parki nson's disease (PD), and (2) to investigate the therapeutic and undesired e ffects 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, allowin g the separation of therapeutic and undesired effects. Eight weeks after bi lateral intracarotid MPTP administration, SKF 82958 (1 mg/kg, n = 4, SKF 82 958, naive group) or methyl-L-DOPA + carbi-dopa (10 + 2.5 mg/kg, n = 4, L-D OPA 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 d ays (SKF 82959, 1 mg/kg, n=4, pretreated). All drug treatments increased th e parameters used classically to evaluate dopaminergic drugs, namely body d isplacement, dyskinesia and dystonia. However, the new detailed analysis re vealed that L-DOPA, but not SKF 82958, had therapeutic effects, reflected b y an increase in goal-directed fore-limb use. SKF 82958, but not L-DOPA, in duced 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 effec ts. Although the effects of SKF 82958 on fore-limb movements, rotational be haviours and body displacement were comparable in the naive and pretreated group, SKF 82958 re-initiated undesired effects in the L-DOPA pretreated gr oup 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 se veral undesired effects. (C) 1999 Lippincott Williams & Wilkins.