title: Endogenous ligands of benzodiazepine binding site have inverse agonistic properties.
abstract: Benzodiazepines have been widely used in clinical praxis for many decades. They act as GABAA receptor agonists and possess muscle-relaxant, hypnotic-sedative, anticonvulsant, and anxiolytic properties. Flumazenil acts as a benzodiazepine receptor antagonist (subunits α1, α2, α3, and α5) or partial agonist (subunits α4 and α6). It competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex, thereby reversing the effects of benzodiazepines. In our experiments, administration of flumazenil in rabbits was surprisingly associated with anxiolytic effects similar to those of midazolam. Additionally, flumazenil significantly and dose-dependently decreased the total number of vocalizations in rats, i.e. it was anxiolytic. These observations seem to be in contrast to the effect of flumazenil in humans, where it is believed to produce mainly anxiogenic effects. It seems that in individuals, who exhibit anxiogenic behavior or in individuals with anticipation anxiety, flumazenil acts as an anxiolytic agent, while in individuals without any signs of anxiety, flumazenil can also act as anxiogenic agent. Thus, we hypothesize that flumazenil is associated with decreased intensity of anticipatory anxiety due to occupancy of benzodiazepine binding sites by an endogenous ligand with inverse agonistic properties.
authors.affiliation: Department of Pharmacology, 2nd Faculty of Medicine, Charles University, V Úvalu 84, Prague 5 150 06, Czech Republic; Department of Pharmacology, 3rd Faculty of Medicine, Charles University, Ruská 87, Prague 10 10034, Czech Republic. Electronic address: jiri.sliva@lfmotol.cuni.cz.
authors.forename: Jiri
authors.initials: J
authors.lastname: Sliva
authors.forename: Ladislav
authors.initials: L
authors.lastname: Hess
authors.forename: Martin
authors.initials: M
authors.lastname: Votava
authors.forename: Jiri
authors.initials: J
authors.lastname: Malek
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy*; D001569:Benzodiazepines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001665:Binding Sites; D005442:Flumazenil / Q000008:administration & dosage / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D011817:Rabbits
chemical_list: D014151:Anti-Anxiety Agents; D058787:GABA-A Receptor Antagonists; D008024:Ligands; D001569:Benzodiazepines; D005442:Flumazenil