Ergoline derivative LEK-8829-induced turning behavior in rats with unilateral striatal ibotenic acid lesions: Interaction with bromocriptine

LEK-8829 [9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8-aminomethylergoli ne bimaleinate] is an antagonist of dopamine D-2 receptors and serotonin (5 -HT)(2) and 5-HT1A receptors in intact animals and a D-1 receptor agonist i n dopamine-depleted animals, In the present study, we used rats with unilat eral striatal lesions with ibotenic acid (IA) to investigate the dopamine r eceptor activities of LEK-8829 in a model with innervated dopamine receptor s, The IA-lesioned rats circled ipsilaterally when challenged with apomorph ine, the mixed agonist on D-1/D-2 receptors. LEK-8829 induced a dose-depend ent contralateral turning that was blocked by D-1 receptor antagonist SCH-2 3390. The treatment with D-1 receptor agonist SKF-82958 induced ipsilateral turning, whereas the treatment with D-1 receptor antagonist haloperidol in duced contralateral posture. The combined treatment with SKF-82958 and halo peridol resulted in a weak contralateral turning, indicating the possible r eceptor mechanism of contralateral turning induced by LEK-8829. Bromocripti ne 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. T he potentiation of turning was blocked either by SCH-23390 or by haloperido l. The potentiation of ipsilateral turning suggests the costimulation of D- 2 and D-1 receptors by bromocriptine and LEK-8829, respectively, whereas th e lack of potentiation by the highest dose of LEK-8829 may be explained by the opposing activity of LEK-8829 and bromocriptine at D-2 receptors. We pr opose that the D-2 and 5HT(2) receptor-blocking and D-1 receptor-stimulatin g profile of LEK-8829 is promising for the treatment of negative symptoms o f schizophrenia.