Serotonergic Activation after 2‐Week Intrastriatal Infusion of l‐Dopa and Slow Recovery of Circling in Rats with Unilateral Nigral Lesions

Abstract

A unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease was used to determine an effective dose to abolish circling behaviour of the continuous intrastriatal infusions of L-dopa via osmotic minipumps into the lesioned striatum. This 2-week L-dopa treatment evoked a dose-dependent decrease in the contralateral rotations induced by acute intraperitoneal L-dopa and carbidopa that was sustained at least for 10 weeks. The minimum effective dose of intrastriatal L-dopa was 3 microg/hr. Striatal [3H]-spiperone binding was significantly increased by the 6-OHDA lesion, reflecting a permanent, lesion-induced, up-regulation of dopamine D2 receptors. Furthermore, striatal dopamine and its metabolites as well as the level of tyrosine hydroxylase were significantly reduced by 6-OHDA. None of these parameters were restored by the 2-week L-dopa infusions but, unexpectedly, the rotational response did not become normalized after discontinuation of L-dopa infusions. Nigral 6-OHDA lesions suppressed ipsilateral striatal 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations, and 5-HT uptake sites while tryptophan hydroxylase was not changed in the striatum. When studying the cause of the sustained circling behaviour, we found that intrastriatal L-dopa infusion dose-dependently elevated striatal tryptophan hydroxylase much above the levels of intact side and 5-HT uptake sites to the level of intact side, but the striatal 5-HT levels exhibited no significant recovery while 5-HIAA levels were partially restored. These data support the view that a long-term ipsilateral activation of the serotonergic innervation occurs after L-dopa infusions into the lesioned striata.