Ergoline Derivative LEK-8829-Induced Turning Behavior in Rats with Unilateral Striatal Ibotenic Acid Lesions: Interaction with Bromocriptine

• Published in: The Journal of pharmacology and experimental therapeutics 1999-03, Vol.288 (3), p.1093
• Main Authors: Sprah, L, Zivin, M, Sket, D
• Format: Article
• Language: English
• Subjects: Animals; Antipsychotic Agents - pharmacology; Behavior, Animal - drug effects; Benzazepines - pharmacology; Bromocriptine - pharmacology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - pathology; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Agonists; Haloperidol - pharmacology; Ibotenic Acid; Lysergic Acid - analogs & derivatives; Lysergic Acid - antagonists & inhibitors; Lysergic Acid - pharmacology; Male; Rats; Rats, Wistar; Receptors, Dopamine - drug effects; Rotation
• ISSN: 0022-3565; 1521-0103

LEK-8829 [9,10-didehydro- N -methyl-(2-propynyl)-6-methyl-8-aminomethylergoline bimaleinate] is an antagonist of dopamine D 2 receptors and serotonin (5-HT) 2 and 5-HT 1A receptors in intact animals and a D 1 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 D 1 /D 2 receptors. LEK-8829 induced a dose-dependent contralateral turning that was blocked by D 1 receptor antagonist SCH-23390. The treatment with D 1 receptor agonist SKF-82958 induced ipsilateral turning, whereas the treatment with D 2 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 D 2 and D 1 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 D 2 receptors. We propose that the D 2 and 5HT 2 receptor-blocking and D 1 receptor-stimulating profile of LEK-8829 is promising for the treatment of negative symptoms of schizophrenia.