Effect of ergot alkaloids on 3H-flunitrazepam binding to mouse brain GABAA receptors.
In vitro effects of dihydroergotoxine, dihydroergosine, dihydroergotamine, alpha-dihydroergocriptine (ergot alkaloids), diazepam, methyl-beta-Carboline-3-carboxilate (beta-CCM), flumazenil (benzodiazepines), gamma-amino butyric acid (GABA) and thiopental (barbiturate) were studied on mouse brain (cerebrum minus cerebral cortex) benzodiazepine binding sites labeled with 3H-flunitrazepam. Specific, high affinity (affinity constant, Kd = 57.7 8.6 nM) binding sites for 3H-flunitrazepam on mouse brain membranes were identified. All benzodiazepine drugs inhibited 3H-flunitrazepam binding with nanomolar potencies. In contrast to benzodiazepines, all ergot drugs, GABA and thiopental produced an enhancement of 3H-flunitrazepam binding to its binding site at the GABAA receptor of the mouse brain. The rank order of potency was: neurotransmitter (GABA) > dihydroergotoxine > thiopental > alpha-dihydroergocriptine > dihydroergosine > dihydroergotamine. The results suggest that dihydrogenated ergot derivatives do not bind to the brain benzodiazepine binding sites labeled with 3H-flunitrazepam. However, an enhancement of 3H-flunitrazepam binding by all ergot drugs tested, clearly identifies an allosteric interaction with the benzodiazepine binding sites of GABAA receptors.
Tvrdeić
Ante
A
Department of Pharmacology, School of Medicine, University of J.J. Strossmayer Osijek, Osijek, Croatia.
Pericić
Danka
D
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism*; D001569:Benzodiazepines; D001921:Brain / Q000378:metabolism*; D004876:Ergot Alkaloids / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008808:Mice, Inbred CBA; D011963:Receptors, GABA-A / Q000378:metabolism*
D014151:Anti-Anxiety Agents; D004876:Ergot Alkaloids; D011963:Receptors, GABA-A; D001569:Benzodiazepines