L-dopa induces dyskinesia in normal monkeys: behavioural and pharmacokinetic observations.

Abstract

RATIONALE:

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.

OBJECTIVES:

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.

• Authors: R K Pearce, M Heikkilä, I B Lindén, P Jenner
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 156 Issue 4 Pg. 402-9 (Aug 2001) ISSN: 0033-3158 [Print] Germany
• PMID: 11498717 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dopamine Agents
• Levodopa

Topics

• Animals
• Behavior, Animal (drug effects)
• Dopamine Agents (blood, pharmacokinetics, pharmacology)
• Dose-Response Relationship, Drug
• Dyskinesia, Drug-Induced (blood, metabolism)
• Female
• Levodopa (blood, pharmacokinetics, pharmacology)
• Macaca fascicularis
• Male
• Movement Disorders (blood, metabolism)