FCE 23884, substrate-dependent interaction with the dopaminergic system. I. Preclinical behavioral studies.
FCE 23884, a newly synthetized ergoline derivative, shows dopamine (DA) agonist or antagonist properties depending on the functional state of the biological substrate. The compound behaves as a full DA antagonist in normal animals, but shows full agonist properties in denervated models in the same dose range. In normal animals, FCE 23884 impairs Sidmans avoidance in rats, reduces spontaneous locomotion in mice and monkeys and antagonizes apomorphine-induced climbing behavior in mice, yawning in rats, emesis in dogs and amphetamine-induced toxicity in grouped mice. After experimental procedures resulting in severe DA depletion, FCE 23884 behaves as a powerful DA-agonist mainly at D-1 receptors. FCE 23884 induces contralateral turning behavior in 6-hydroxydopamine-lesioned rats and reverses 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced akinesia in monkeys and reserpine-induced hypokinesia in mice. These results indicate that the antagonist or agonist activity of FCE 23884 is substrate-dependent and mostly related to the presence or absence of DA. This leads to the apparently paradoxical suggestion that the compound could be useful both in psychotic states and extrapyramidal diseases, i.e., in clinical conditions characterized by either excessive or impaired DAergic neurotransmission.
R&D Farmitalia Carlo Erba-Erbamont Group, Central Nervous System Department, Nerviano, MI, Italy.
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D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D002144:Callithrix; D004285:Dogs; D015259:Dopamine Agents / Q000494:pharmacology*; D018492:Dopamine Antagonists; D004347:Drug Interactions; D004873:Ergolines / Q000494:pharmacology*; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D004873:Ergolines; C071320:FCE 23884; D001058:Apomorphine