ANTIPARKINSONIAN POTENTIAL OF INTERACTION OF LEK-8829 WITH BROMOCRIPTINE

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.