Abstract

LEK-8829 [9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8-aminomethylergoline bimaleinate] is an antagonist of dopamine D₂ receptors and serotonin (5-HT)₂ and 5-HT_1A receptors in intact animals and a D₁ receptor agonist in dopamine-depleted animals. In the present study, we used rats with unilateral striatal lesions with ibotenic acid (IA) to investigate the dopamine receptor activities of LEK-8829 in a model with innervated dopamine receptors. The IA-lesioned rats circled ipsilaterally when challenged with apomorphine, the mixed agonist on D₁/D₂ receptors. LEK-8829 induced a dose-dependent contralateral turning that was blocked by D₁receptor antagonist SCH-23390. The treatment with D₁receptor agonist SKF-82958 induced ipsilateral turning, whereas the treatment with D₂ receptor antagonist haloperidol induced contralateral posture. The combined treatment with SKF-82958 and haloperidol resulted in a weak contralateral turning, indicating the possible receptor mechanism of contralateral turning induced by LEK-8829. Bromocriptine induced a weak ipsilateral turning that was blocked by haloperidol. The ipsilateral turning induced by bromocriptine was significantly potentiated by the coadministration of a low dose but not by a high dose of LEK-8829. The potentiation of turning was blocked either by SCH-23390 or by haloperidol. The potentiation of ipsilateral turning suggests the costimulation of D₂ and D₁ receptors by bromocriptine and LEK-8829, respectively, whereas the lack of potentiation by the highest dose of LEK-8829 may be explained by the opposing activity of LEK-8829 and bromocriptine at D₂ receptors. We propose that the D₂ and 5HT₂ receptor-blocking and D₁ receptor-stimulating profile of LEK-8829 is promising for the treatment of negative symptoms of schizophrenia.