M. Zivin et al., ANTIPARKINSONIAN POTENTIAL OF INTERACTION OF LEK-8829 WITH BROMOCRIPTINE, European journal of pharmacology, 349(2-3), 1998, pp. 151-157
The ergoline derivative, LEK-8829 thyl-(2-propynyl)-6-methyl-8-aminome
thylergoline), has been proposed as a potential atypical antipsychotic
drug with antagonistic actions at dopamine D-2 and serotonin 5-HT2 an
d 5-HT1A receptors (Krisch et al., 1994, 1996). LEK-8829 also induces
contralateral turning in rats with 6-hydroxydopamine-induced unilatera
l lesion of dopamine nigrostriatal neurons. Turning is blocked by SCH-
23390 hyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), a dopamine D-
1 receptor antagonist. It has been suggested that LEK-8829 could have
beneficial effects in parkinsonian patients suffering from psychotic e
pisodes induced as a side-effect of antiparkinsonian treatment with do
pamine D-2 receptor agonists. Therefore, we now investigated the inter
action of LEK-8829 with the dopamine D-2 receptor agonist bromocriptin
e (2-bromo-alpha-ergokryptine) in 6-hydroxydopamine-lesioned rats. Tre
atment with either LEK-8829 (3 mg kg(-1)) or bromocriptine (3 mg kg(-1
)) induced a vigorous contralateral turning response. The cumulated nu
mber of turns induced by the treatment with both drugs combined was no
t significantly different from the cumulated number of turns induced b
y single-drug treatment. The pretreatment with SCH-23390 (1 mg kg(-1))
did not have a significant effect on the bromocriptine-induced turnin
g but significantly decreased the turning observed after the combined
LEK-8829/bromocriptine treatment. We conclude that in the 6-hydroxydop
amine model, the turning behaviour mediated by the LEK-8829/bromocript
ine combination may be the result of opposing activity of both drugs a
t dopamine D-2 receptors with concomitant stimulation of dopamine D-1
receptors by LEK-8829. Therefore, LEK-8829 may have a potential for th
e therapy of parkinsonism complicated by dopamine D-2 receptor agonist
drug-induced psychosis. (C) 1998 Elsevier Science B.V. All rights res
erved.