The validity of the pretreated, unilaterally MPTP-treated monkeys as a model of Parkinson's disease: a detailed behavioural analysis of the therapeutic and undesired effects of the D2 agonist quinpirole and the D1 agonist SKF 81297.
The goal of this study was to evaluate the validity of the pretreated, unilaterally MPTP-treated monkey as an animal model of Parkinson's disease (PD). For that purpose, a detailed ethogram was developed and assessed in four male rhesus monkeys that had received MPTP (2.5 mg) in the carotid artery contralateral to the dominant limb. Subsequently, the behavioural effects of the dopamine D2 agonist quinpirole and the dopamine D1 agonist SKF 81297 were studied. The ethogram was found to allow a clear-cut and objective separation of drug-induced behaviours into therapeutic and undesired effects in the MPTP-treated monkeys. Saline-treated monkeys predominantly displayed ipsilateral goal-directed fore-limb movements, and distinct types of ipsilaterally directed rotations. Although quinpirole and SKF 81297 increased motor behaviours, such as body displacement, contralateral fore-limb movements and contralateral rotational behaviours, assessment of the new detailed ethogram revealed that this increase was completely due to the activation of abnormal, non-goal-directed behaviours, such as dyskinetic fore-limb movements, pivoting and shuffling. Moreover, the new ethogram made clear that the drug treatments induced not only dyskinesia and dystonia, but also epileptoid behaviour, which was confirmed by EEG analysis. In summary, the detailed behavioural analysis showed that this model does not adequately predict the clinical effects of the D2 agonist. It is concluded that the pretreated, unilaterally MPTP-treated monkey is not a valid model to predict the therapeutic and undesired effects of dopaminergic drugs in humans.
Andringa
G
G
Research Institute Neuroscience, Department of Neurology, Vrije Universiteit of Amsterdam, The Netherlands.
Vermeulen
R J
RJ
Drukarch
B
B
Renier
W O
WO
Stoof
J C
JC
Cools
A R
AR
D000818:Animals; D001132:Arm / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000627:therapeutic use*; 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; 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; D019257:Quinpirole / Q000627:therapeutic use*; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D015203:Reproducibility of Results
D001552:Benzazepines; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D019257:Quinpirole; C067113:SK&F 81297