The D1 receptor-mediated effects of the ergoline derivative LEK-8829 in rats with unilateral 6-hydroxydopamine lesions.

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 6OHDA model, we used in situ hybridization histochemistry to compare the effect of SCH-23390 pretreatment 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 antipsychotic LEK-8829 may prove useful as an experimental tool for the study of D1:D2 receptor interactions and could have beneficial effects in the treatment of drug-induced psychosis in patients with Parkinson's disease.

• Authors: M Zivin, L Sprah, D Sket
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 119 Issue 6 Pg. 1187-96 (Nov 1996) ISSN: 0007-1188 [Print] England
• PMID: 8937722 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antipsychotic Agents
• Benzazepines
• Receptors, Dopamine D1
• LEK 8829
• Oxidopamine
• Pindolol
• Lysergic Acid
• Haloperidol
• Apomorphine

Topics

• Animals
• Antipsychotic Agents (pharmacology)
• Apomorphine (pharmacology)
• Behavior, Animal (drug effects)
• Benzazepines (pharmacology)
• Dose-Response Relationship, Drug
• Genes, fos (drug effects)
• Haloperidol (pharmacology)
• Lysergic Acid (analogs & derivatives, pharmacology)
• Male
• Oxidopamine
• Pindolol (pharmacology)
• Rats
• Rats, Wistar
• Receptors, Dopamine D1 (drug effects, physiology)