The effects of chronic levodopa treatment on pre- and postsynaptic markers of dopaminergic function in striatum of parkinsonian monkeys.

Abstract

Therapeutic treatment of parkinsonian monkeys by chronic administration of levodopa (l-DOPA) leads to the development of dyskinesias and other motor fluctuations. It is unclear whether there are alterations in the dopamine system that are related to the induction of dyskinesias by l-DOPA, but recent attention has focused on the D1 receptor system. The present study assessed the consequences of chronic l-DOPA treatment in monkeys made parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on indices of the pre- and post-synaptic dopamine (DA) system. Treatment with therapeutic doses of l-DOPA led to the induction of dyskinesias in the MPTP-treated monkeys. High-pressure liquid chromatography was used for measurement of tissue levels of DA and its metabolites, and quantitative autoradiography was used to examine the regional integrity of the presynaptic DA system (by measuring [3H]mazindol binding to DA uptake sites). Quantitative autoradiography was used to measure the number of postsynaptic D1 receptors (using [3H] SCH 23390) in the striatum and pallidum of normal, MPTP alone, and MPTP monkeys treated chronically with l-DOPA. In both MPTP-treated monkeys, levels of DA and metabolites as well as [3H]mazindol binding were greatly reduced in the caudate and putamen, slightly more in dorsal than in ventral areas. However, the lack of increase in striatal DA levels along with higher [3H]mazindol binding in MPTP-plus-l-DOPA-treated monkeys suggested differences in the way DA was used after l-DOPA treatment In MPTP-treated monkeys, a significant increase (141-170% of normals) of D1 receptor numbers was observed in putamen and dorsal caudate. With l-DOPA treatment, the number of D1 receptor numbers was further elevated in caudal putamen (119-123%), dorsal caudate (110-130%), and in the internal segment of the globus pallidus (GPi; 164% of normals) of MPTP-treated monkeys as compared with MPTP treatment alone. This suggested that in MPTP-treated monkeys made dyskinetic by chronic pulsatile delivery of l-DOPA, there was enhanced production of D1 receptors in the direct striatal output to the GPi.