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.