Levodopa biotransformation in hemi-Parkinson rats: effect of dopamine receptor agonists and antagonists

Abstract

We investigated the effects of continuous perfusion of dopamine D 1 and D 2 receptor agonists and antagonists on the biotransformation of locally applied levodopa (L-DOPA) to dopamine in the striatum of freely moving hemi-Parkinson rats by means of in vivo microdialysis. The extent of the lesion was shown to influence dopamine formation after L-DOPA administration. In partially denervated striatum there was a more ‘physiological’ conversion, whereas in extensively denervated striatum extracellular dopamine increased to excessively high levels after L-DOPA. The dopamine D 2 receptor agonist quinpirole (10 μM) attenuated the L-DOPA-induced (2 μM) dopamine release in intact, partially denervated and extensively denervated striatum. The dopamine D 1 receptor antagonist SCH 23390 ( R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine hydrochloride) (10 μM) caused effects similar to those of quinpirole. However, in intact striatum it acted as the dopamine D 2 receptor antagonist (−)-sulpiride and the dopamine D 1 receptor agonist CY 208243 (((−),4,6,6a,7,8,12b-hexahydro-7-methyl-indolo-(4,3- ab)phenanthoridine), showing no effect on L-DOPA biotransformation. The data suggest that dopamine D 2 receptor agonists and possibly dopamine D 1 receptor antagonists will be beneficial in the treatment of Parkinson's disease, probably by keeping extracellular levels of dopamine at more ‘physiological’ levels. This may enable a reduction of L-DOPA doses and therefore may prevent dyskinesias at a later stage of the disease.