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.
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.
Division of Pharmacology and Therapeutics, Guy's, King's, and St Thomas' School of Biomedical Sciences, King's College, London, United Kingdom.
Lance A
LA
Smith
Michael J
MJ
Jackson
Matthew J
MJ
Hansard
Eleni
E
Maratos
Peter
P
Jenner
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects*; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology*; D002144:Callithrix; D002230:Carbidopa / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D002396:Catechols / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000209:etiology* / Q000517:prevention & control*; D005260:Female; D007980:Levodopa / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009570:Nitriles; D020734:Parkinsonian Disorders / Q000517:prevention & control*; D020551:Pulse Therapy, Drug / Q000379:methods*; D013378:Substantia Nigra / Q000187:drug effects*; D013997:Time Factors
D000978:Antiparkinson Agents; D002396:Catechols; D009570:Nitriles; D007980:Levodopa; C071192:entacapone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D002230:Carbidopa