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

被引:16
作者
Sarre, S
Ebinger, G
Michotte, Y
机构
[1] FREE UNIV BRUSSELS,INST PHARMACEUT,DEPT PHARMACEUT CHEM & DRUG ANAL,B-1090 BRUSSELS,BELGIUM
[2] FREE UNIV BRUSSELS HOSP,DEPT NEUROL,BRUSSELS,BELGIUM
关键词
dopamine; levodopa; microdialysis; Parkinson's disease; dopamine receptor agonist; dopamine receptor antagonist;
D O I
10.1016/0014-2999(95)00715-6
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 mu M) attenuated the L-DOPA-induced (2 mu M) 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-(1H)-3-benzazepine hydrochloride) (10 mu M) 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.
引用
收藏
页码:247 / 260
页数:14
相关论文
共 47 条
[1]   EFFECTS OF L-DOPA ON EXTRACELLULAR DOPAMINE IN STRIATUM OF NORMAL AND 6-HYDROXYDOPAMINE-TREATED RATS [J].
ABERCROMBIE, ED ;
BONATZ, AE ;
ZIGMOND, MJ .
BRAIN RESEARCH, 1990, 525 (01) :36-44
[2]  
Agid Y., 1987, MOVEMENT DISORD, V2, P166
[3]   BRAIN MICRODIALYSIS [J].
BENVENISTE, H .
JOURNAL OF NEUROCHEMISTRY, 1989, 52 (06) :1667-1679
[4]  
BERNHEIMER H, 1973, J NEUROL SCI, V20, P415, DOI 10.1016/0022-510X(73)90175-5
[5]   D1 AND D2 DOPAMINERGIC REGULATION OF ACETYLCHOLINE-RELEASE FROM STRIATA OF FREELY MOVING RATS [J].
BERTORELLI, R ;
CONSOLO, S .
JOURNAL OF NEUROCHEMISTRY, 1990, 54 (06) :2145-2148
[6]   BROMOCRIPTINE IN PARKINSONISM [J].
CALNE, DB ;
TEYCHENNE, PF ;
CLAVERIA, LE ;
EASTMAN, R ;
GREENACRE, JK ;
PETRIE, A .
BMJ-BRITISH MEDICAL JOURNAL, 1974, 4 (5942) :442-444
[7]  
CARLSSON A, 1975, PRE POSTSYNAPTIC REC, P49
[8]   PARTIAL LESION OF THE SUBSTANTIA-NIGRA - RELATION BETWEEN EXTENT OF LESION AND ROTATIONAL BEHAVIOR [J].
CARMAN, LS ;
GAGE, FH ;
SHULTS, CW .
BRAIN RESEARCH, 1991, 553 (02) :275-283
[9]  
CASTANEDA E, 1990, J NEUROSCI, V10, P1847
[10]   LEVODOPA INDUCTION OF FOS IMMUNOREACTIVITY IN RAT-BRAIN FOLLOWING PARTIAL AND COMPLETE LESIONS OF THE SUBSTANTIA-NIGRA [J].
COLE, DG ;
GROWDON, JH ;
DIFIGLIA, M .
EXPERIMENTAL NEUROLOGY, 1993, 120 (02) :223-232