Effect of pulsatile administration of levodopa on dyskinesia induction in drug‐naïve MPTP‐treated common marmosets: Effect of dose, frequency of administration, and brain exposure

Abstract

Levodopa (L‐dopa) consistently primes basal ganglia for the appearance of dyskinesia in parkinsonian patients and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine hydrochloride (MPTP) ‐treated primates. This finding may reflect its relatively short duration of effects resulting in pulsatile stimulation of postsynaptic dopamine receptors in the striatum. We have compared the relationship between L‐dopa dose and frequency of administration on dyskinesia initiation in drug‐naïve, MPTP‐treated common marmosets. We have also studied the effect of increased brain exposure to pulsatile administration by combining a low‐dose of L‐dopa with the peripheral catechol‐O‐methyltransferase inhibitor (COMT‐I), entacapone. Pulsatile administration of a low (dose range, 5.0–7.5 mg/kg p.o.) or a high (12.5 mg/kg) dose of L‐dopa plus carbidopa b.i.d. produced a dose‐related reversal of motor deficits. Repeated administration of low and high doses of L‐dopa for 26 days to drug‐naïve, MPTP‐treated animals also caused a dose‐related induction of peak‐dose dyskinesia. Repeated administration of high‐dose L‐dopa b.i.d. compared to once daily caused a frequency‐related improvement of motor symptoms, resulting in a more rapid and initially more intense appearance of peak‐dose dyskinesia. Administration of low‐dose L‐dopa b.i.d. for 26 days in combination with entacapone enhanced the increase in locomotor activity and reversal of disability produced by L‐dopa alone, but with no obvious change in duration of L‐dopa's effect. However, combining entacapone with L‐dopa resulted in the more rapid appearance of dyskinesia, which was initially more severe than occurred with L‐dopa alone. Importantly, increasing pulsatile exposure of brain to L‐dopa by preventing its peripheral breakdown also increases dyskinesia induction. © 2003 Movement Disorder Society