L-dopa induces dyskinesia in normal monkeys: behavioural and pharmacokinetic observations.
BACKGROUND
L-Dopa induces dyskinesias during the treatment of Parkinson's disease and also in primates with nigrostriatal lesions produced by MPTP, but it is claimed that L-dopa does not provoke dyskinesia in humans or monkeys with an intact or mildly damaged nigrostriatal system.


OBJECTIVE
This study assessed the behavioural and pharmacokinetic effects of chronic oral administration of L-dopa plus carbidopa alone, or with co-administration of the peripheral COMT inhibitor entacapone, to normal macaque monkeys. Repeated high dose L-dopa administration was shown to induce marked dyskinesias in monkeys with an intact nigrostriatal system, and the threshold for dyskinesia expression was increased by peripheral catechol-O-methyltransferase inhibition with entacapone.


METHODS
Six groups of normal macaque monkeys (n=8 per group; Macaca fascicularis) were treated with L-dopa (20, 40 or 80 mg/kg) plus carbidopa (5, 10 or 20 mg/kg) with or without the catechol-O-methyltransferase inhibitor entacapone (20, 40 or 80 mg/kg), or with entacapone alone (80 mg/kg), by oral administration once daily for 13 weeks.


RESULTS
Eleven of 16 animals receiving high dose L-dopa (80 mg/kg plus carbidopa 20 mg/kg PO with or without entacapone 80 mg/kg PO for 13 weeks) gradually developed reproducible and idiosyncratic combinations of chorea, athetosis and dystonia maximal at 60-100 min after L-dopa administration, which progressively intensified over the course of the study. The dyskinesias observed were similar in type and distribution to L-dopa-induced dyskinesia observed in patients with Parkinson's disease and in MPTP-treated primates. The occurrence of dyskinesia correlated with plasma concentrations of L-dopa, with animals displaying the most severe dyskinesias having significantly higher plasma concentrations of L-dopa one hour after dosing than animals with mild or moderate dyskinesia or no dyskinesia. Co-administration of entacapone with L-dopa plus carbidopa significantly lowered peak plasma concentrations of L-dopa and this was reflected by a decrease in the severity of dyskinesias, with only one animal receiving entacapone and high dose L-dopa plus carbidopa showing severe dyskinesia, while four receiving high dose L-dopa plus carbidopa alone did so.


CONCLUSIONS
These results show for the first time that chronic oral L-dopa administration can provoke dyskinesias in primates independently of nigrostriatal damage, and that this effect is dose related.
Pearce
R K
RK
Neurodegenerative Diseases Research Centre, Hodgkin Building, Division of Pharmacology and Therapeutics, GKT School of Biomedical Sciences, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK.
Heikkilä
M
M
Lindén
I B
IB
Jenner
P
P
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015259:Dopamine Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000097:blood / Q000378:metabolism*; D005260:Female; D007980:Levodopa / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D009069:Movement Disorders / Q000097:blood / Q000378:metabolism
D015259:Dopamine Agents; D007980:Levodopa