LEK-8829

Parkinsonism, a common unwanted side effect of typical antipsychotic (neuroleptic) drugs, is induced by the blockade of striatal dopamine D2 receptors. In rats with hemi-parkinsonism induced by unilateral lesion of dopaminergic nigrostriatal neurons with 6-hydroxydopamine, D2 antagonists inhibit contralateral turning induced by D2 agonists and augment the levels of neurotensin mRNA in dopaminergically intact striatum. By contrast, D1 agonists induce contralateral turning and augment neurotensin mRNA levels in dopamine-depleted striatum. These effects could be inhibited by D1 but not by D2 antagonists. Here we used a hemi-parkinsonian model to investigate the effects of putative D1 agonist/D2 antagonist LEK-8829 (9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8-aminomethylergoline bimaleinate), an experimental antipsychotic, on turning behavior and the expression of striatal neurotensin, preprotachykinin and neurotransmitter-induced early gene protein 4 (ania-4) mRNAs. We found that LEK-8829 inhibited contralateral turning induced by D2 agonist quinpirole, but only if the rats were cotreated with D1 antagonist SCH-23390. In situ hybridization showed that LEK-8829 induced the expression of neurotensin and ania-4 mRNAs in dopamine-intact striatum that could be completely blocked only by the combined treatment with SCH-23390 and quinpirole. In addition, LEK-8829 augmented the expression of neurotensin, preprotachykinin and ania-4 mRNAs in dopamine-depleted striatum that could be completely blocked by SCH-23390. This study clearly demonstrates that in hemi-parkinsonian rats D1 agonistic activity of LEK-8829 confers its anti-parkinsonian drug-like properties and modulates its neuroleptic drug-like properties, which are dependent on the blockade of dopamine D2 receptors. These findings imply that atypical antipsychotics with D1 intrinsic activity might have a reduced propensity for the induction of extrapyramidal syndrome.

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-HT1A 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 D1 receptor antagonist SCH-23390. The treatment with D1 receptor 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.