Levodopa biotransformation in hemi-Parkinson rats: effect of dopamine receptor agonists and antagonists.
We investigated the effects of continuous perfusion of dopamine D1 and D2 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 D2 receptor agonist quinpirole (10 mu M) attenuated the L-DOPA-induced (2 mu M) dopamine release in intact, partially denervated and extensively denervated striatum. The dopamine D1 receptor antagonist SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-(1H)-3- benzazepine hydrochloride) (10 mu M) caused effects similar to those of quinpirole. However, in intact striatum it acted as the dopamine D2 receptor antagonist (-)-sulpiride and the dopamine D1 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 D2 receptor agonists and possibly dopamine D1 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.
Sarre
S
S
Department of Pharmaceutical Chemistry and Drug Analysis, Pharmaceutical Institute, Vrije Universiteit Brussel, Belgium.
Ebinger
G
G
Michotte
Y
Y
D000818:Animals; D000978:Antiparkinson Agents / Q000493:pharmacokinetics*; D001552:Benzazepines / Q000494:pharmacology; D001711:Biotransformation; D003342:Corpus Striatum / Q000502:physiology; D003714:Denervation; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D007980:Levodopa / Q000493:pharmacokinetics*; D008297:Male; D010300:Parkinson Disease / Q000378:metabolism*; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013469:Sulpiride / Q000494:pharmacology
D000978:Antiparkinson Agents; D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D019257:Quinpirole; D007980:Levodopa; D013469:Sulpiride