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

G Andringa, L Lubbers, B Drukarch, J C Stoof, A R Cools

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)175-82
Number of pages8
JournalBehavioural pharmacology
Volume10
Issue number2
Publication statusPublished - Mar 1999

Cite this

@article{ae30f09eb72748a889c038eb7b0de87b,
title = "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.",
keywords = "Animals, Antiparkinson Agents, Arm, Behavior, Animal, Benzazepines, Dopamine Agents, Dopamine Agonists, Dyskinesia, Drug-Induced, Dystonia, Electroencephalography, Epilepsy, Levodopa, MPTP Poisoning, Macaca mulatta, Male, Motor Activity, Movement, Parkinson Disease, Secondary, Predictive Value of Tests, Receptors, Dopamine D1, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.",
author = "G Andringa and L Lubbers and B Drukarch and Stoof, {J C} and Cools, {A R}",
year = "1999",
month = "3",
language = "English",
volume = "10",
pages = "175--82",
journal = "Behavioural pharmacology",
issn = "0955-8810",
publisher = "Lippincott Williams and Wilkins Ltd.",
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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. / Andringa, G; Lubbers, L; Drukarch, B; Stoof, J C; Cools, A R.

In: Behavioural pharmacology, Vol. 10, No. 2, 03.1999, p. 175-82.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The predictive validity of the drug-naive bilaterally MPTP-treated monkey as a model of Parkinson's disease

T2 - effects of L-DOPA and the D1 agonist SKF 82958

AU - Andringa, G

AU - Lubbers, L

AU - Drukarch, B

AU - Stoof, J C

AU - Cools, A R

PY - 1999/3

Y1 - 1999/3

N2 - 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.

AB - 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.

KW - Animals

KW - Antiparkinson Agents

KW - Arm

KW - Behavior, Animal

KW - Benzazepines

KW - Dopamine Agents

KW - Dopamine Agonists

KW - Dyskinesia, Drug-Induced

KW - Dystonia

KW - Electroencephalography

KW - Epilepsy

KW - Levodopa

KW - MPTP Poisoning

KW - Macaca mulatta

KW - Male

KW - Motor Activity

KW - Movement

KW - Parkinson Disease, Secondary

KW - Predictive Value of Tests

KW - Receptors, Dopamine D1

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, P.H.S.

M3 - Article

VL - 10

SP - 175

EP - 182

JO - Behavioural pharmacology

JF - Behavioural pharmacology

SN - 0955-8810

IS - 2

ER -