Repeated administration of piribedil induces less dyskinesia than L-dopa in MPTP-treated common marmosets: a behavioural and biochemical investigation.

Abstract

Piribedil ([1-(3,4-methylenedioxybenzyl)-4-(2-pyrimidinyl)piperazine]; S 4200) is a dopamine agonist with equal affinity for D(2)/D(3) dopamine receptors effective in treating Parkinson's disease as monotherapy or as an adjunct to levodopa (L-dopa). However, its ability to prime basal ganglia for the appearance of dyskinesia is unknown. We now report on the ability of repeated administration of piribedil to induce dyskinesia in drug naïve 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -lesioned common marmosets compared with L-dopa and its actions on the direct and indirect striatal outflow pathways. Administration of piribedil (4.0-5.0 mg/kg orally) or L-dopa (12.5 mg/kg orally plus carbidopa 12.5 mg/kg orally twice daily) produced equivalent increases in locomotor activity and reversal of motor deficits over a 28-day study period. Administration of L-dopa resulted in the progressive development of marked dyskinesia over the period of study. In contrast, administration of piribedil produced a significantly lower degree and intensity of dyskinesia. Surprisingly, piribedil caused an increase in vigilance and alertness compared to L-dopa, which may relate to the recently discovered alpha(2)-noradrenergic antagonist properties of piribedil. The behavioural differences between piribedil and L-dopa are reflected in the biochemical changes associated with the direct striatal output pathway. Administration of L-dopa or piribedil did not reverse the MPTP-induced up-regulation of preproenkephalin A mRNA in rostral or caudal areas of the putamen or caudate nucleus. In contrast, administration of either piribedil or L-dopa reversed the downregulation of preprotachykinin mRNA induced by MPTP in rostral and caudal striatum. L-dopa, but not Piribedil, reversed the decrease in preproenkephalin B mRNA produced by MPTP treatment.

• Authors: Lance A Smith, Banu C Tel, Michael J Jackson, Matthew J Hansard, Rogelio Braceras, Céline Bonhomme, Claire Chezaubernard, Susanna Del Signore, Sarah Rose, Peter Jenner
• Journal: Movement disorders : official journal of the Movement Disorder Society (Mov Disord) Vol. 17 Issue 5 Pg. 887-901 (Sep 2002) ISSN: 0885-3185 [Print] United States
• PMID: 12360537 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2002 Movement Disorder Society

Chemical References

• Antiparkinson Agents
• RNA, Messenger
• Levodopa
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Piribedil

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (adverse effects)
• Animals
• Antiparkinson Agents (administration & dosage, adverse effects, therapeutic use)
• Arousal (drug effects)
• Callithrix
• Caudate Nucleus (metabolism)
• Corpus Striatum (metabolism)
• Culture Techniques
• Drug Administration Schedule
• Dyskinesia, Drug-Induced (etiology)
• Dyskinesias (diagnosis, drug therapy, metabolism)
• Female
• In Situ Hybridization
• Levodopa (adverse effects)
• Locomotion (drug effects)
• Male
• Piribedil (administration & dosage, adverse effects, therapeutic use)
• RNA, Messenger (metabolism)
• Severity of Illness Index
• Time Factors