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.

Abstract

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.

• Authors: G Andringa, L Lubbers, B Drukarch, J C Stoof, A R Cools
• Journal: Behavioural pharmacology (Behav Pharmacol) Vol. 10 Issue 2 Pg. 175-82 (Mar 1999) ISSN: 0955-8810 [Print] England
• PMID: 10780830 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antiparkinson Agents
• Benzazepines
• Dopamine Agents
• Dopamine Agonists
• Receptors, Dopamine D1
• Levodopa
• SK&F 82958

Topics

• Animals
• Antiparkinson Agents (therapeutic use)
• Arm (physiology)
• Behavior, Animal (drug effects)
• Benzazepines (therapeutic use)
• Dopamine Agents (toxicity)
• Dopamine Agonists (therapeutic use)
• Dyskinesia, Drug-Induced (drug therapy, psychology)
• Dystonia (drug therapy, psychology)
• Electroencephalography (drug effects)
• Epilepsy (psychology)
• Levodopa (therapeutic use)
• MPTP Poisoning (drug therapy, psychology)
• Macaca mulatta
• Male
• Motor Activity (drug effects)
• Movement (drug effects)
• Parkinson Disease, Secondary (chemically induced, drug therapy, psychology)
• Predictive Value of Tests
• Receptors, Dopamine D1 (agonists)