| Author/Editor | Živin, M; Šprah, L; Sket, D | |
| Title | The D1 receptor-mediated effects of the ergoline derivative LEK-8829 in rats with unilateral 6-hydroxydopamine lesions | |
| Type | članek | |
| Source | Br J Pharmacol | |
| Vol. and No. | Letnik 119 | |
| Publication year | 1996 | |
| Volume | str. 1187-96 | |
| Language | eng | |
| Abstract | 1. Previous experiments have suggested a potential atypical antipsychotic activity of the ergoline derivative LEK-8829. In vitro experiments showed a high affinity to 5-HT1A, 5-HT2 and D2 receptors (the ratio of pKi values 5-HT2/D2=1.11) and a moderate affinity to D1 receptors. In vivo experiments showed antagonism of dopamine and 5-hydroxytryptamine (5-HT) receptor-linked behaviours. 2. In the present study, the rats with unilateral dopaminergic deafferentation of the striatum, induced by the lesion of the median forebrain bundle with 6-hydroxydopamine (6-OHDA), were used to determine the effects of LEK-8829 on turning behaviour and on striatal c-fos mRNA levels. 3. The administration of LEK-8829 induced a long lasting contralateral turning behaviour that was dose-dependent. It was found that the specific D1 receptor antagonist SCH-23390 but not the D2 receptor antagonist haloperidol or 5-HT1A antagonist pindolol, dose-dependently inhibited the turning behaviour induced by LEK-8829. 4. In an attempt to clarify the D1:D2 receptor interactions involved in the action of LEK-8829 in the 6-OHDA model, we used in situ hybridization histochemistry to compare the effect of SCH-23390 preatment on striatal c-fos mRNA expression induced either by LEK-8829 or by the typical antipsychotic haloperidol. 5. LEK- 8829 induced a bilateral striatal c-fos mRNA expression that was significantly higher in the denervated striatum as compared to the intact striatum and was completely blocked on both sides by pretreatment with SCH-23390. In contrast, haloperidol-induced striatal c-fos mRNA expression was limited to the innervated striatum and was not blocked by SCH-23390. 6. Our data demonstrate an intrinsic activity of LEK-8829 on D1 receptors that is potentiated in the dopamine-depleted striatum. We conclude, therefore, that the putative atypical antipsyxhotic LEK-8829 may prove useful as an experimental tool for the study of D1:D2 receptor. | |
| Descriptors | ERGOLINES DOPAMINE AGONISTS DOPAMINE ANTAGONISTS RECEPTORS, DOPAMINE D1 CORPUS STRIATUM RATS DOSE-RESPONSE RELATIONSHIP, DRUG HYDROXYDOPAMINES HALOPERIDOL PINDOLOL RNA, MESSENGER NEOSTRIATUM BEHAVIOR, ANIMAL IN SITU HYBRIDIZATION AUTORADIOGRAPHY |