This study was designed to elucidate the mechanism to develop levodopa-induced dyskinesia in patients with Parkinson's disease. For this purpose, we administered methyl levodopa repeatedly to a rat model of Parkinson's disease with unilateral 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal dopamine pathway. After a washout period, we measured apomorphine sensitivity of contralateral rotation and made parallel determination of Fos expression in the caudate-putamen and globus pallidus of the same animal. Once daily, i.p. injection of methyl levodopa plus benserazide for 10 days increased the number of rotations over time. A challenge dose of apomorphine showed enhanced rotational response in rats pretreated with methyl levodopa. Repeated administration of methyl levodopa resulted in diminished apomorphine sensitivity of Fos expression in the dopamine depleted caudate-putamen and in enhanced sensitivity in the globus pallidus of the same side. Present results may add evidence to the idea that repeated administration of levodopa develops dopaminergic sensitization mediated by augmented activation of pallidal neurons involved in D2-responsive pallidal output pathway. (C) 2000 Elsevier Science Ireland Ltd.