Cabergoline, a long-acting dopamine D-2-like receptor agonist, produces a sustained antiparkinsonian effect with transient dyskinesias in parkinsonian drug-naive primates

被引:56
作者
Grondin, R
Goulet, M
DiPaolo, T
Bedard, PJ
机构
[1] UNIV LAVAL,FAC MED,DEPT PHARMACOL,QUEBEC CITY,PQ G1J 1Z4,CANADA
[2] HOP ENFANTS JESUS,NEUROBIOL RES CTR,QUEBEC CITY,PQ G1J 1Z4,CANADA
[3] UNIV LAVAL,SCH PHARM,ST FOY,PQ G1V 4G2,CANADA
[4] UNIV LAVAL,MED CTR,DEPT MOL ENDOCRINOL,ST FOY,PQ G1V 4G2,CANADA
关键词
Parkinson's disease; MPTP; dyskinesia; cabergoline; GABA(A) receptor; dopamine D-2 receptor;
D O I
10.1016/0006-8993(96)00597-5
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Continuous dopaminergic receptor stimulation is now considered as an interesting approach for the control of motor complications often seen in parkinsonian patients treated chronically with levodopa. Cabergoline, which is a long-acting dopamine D-2-like receptor agonist, has been tried recently with good results as an adjunct in patients already on levodopa-therapy. Thus, the present study was designed to test the effects of repeated s.c administration of cabergoline as sole therapeutic agent during a month in 3 drug-naive MPTP parkinsonian monkeys to see whether or not cabergoline, given every other day at 0.25 mg/kg, would have a sustained antiparkinsonian effect and would induce dyskinesias. The animals were rated to quantify the antiparkinsonian as well as the dyskinetic response and gross locomotor activity was monitored by photocells. The averaged locomotor response, initially greatly increased (similar to 9 times higher than after saline treatment in the same animals), decreased by similar to 50% after 2 weeks but was thereafter maintained at this level until the end of the study. The parkinsonian features were improved in a sustained manner in all monkeys and transient dyskinesias (week 1 and 2) were present in 2 of 3 monkeys. After sacrifice receptor binding assays were performed on striatal and pallidal tissues homogenates with tritiated selective ligands and compared with those of 3 normal and 3 MPTP-exposed monkeys otherwise untreated. A significant decrease in dopamine D-2-like receptor density in the putamen (- 36% on average vs. untreated MPTP-exposed monkeys) may be involved in the behavioral partial tolerance to antiparkinsonian effect of cabergoline and the disappearance of dyskinesias. A reversal of the supersensitivity of GABA(A) receptor in the internal segment of the globus pallidus (-15% on average vs. untreated MPTP-exposed monkeys) may also be implicated in this latter behavioral effect.
引用
收藏
页码:298 / 306
页数:9
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