Portal de Periódicos da CAPES

The anxiolytic-like effects of the neurosteroid allopregnanolone: interactions with GABAA receptors

1997; Elsevier BV; Volume: 325; Issue: 1 Linguagem: Inglês

10.1016/s0014-2999(97)00096-4

1879-0712

Michelle D. Brot, Yvette Akwa, Robert H. Purdy, George F. Koob, Karen T. Britton,

Receptor Mechanisms and Signaling

The neurosteroid 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) was administered systemically to rats which were tested in the Geller-Seifter conflict paradigm, an established animal model of anxiety. Allopregnanolone was found to produce significant anxiolytic-like effects at a dose of 8 mg/kg. When three ligands that function at different sites on the γ-aminobutyric acid/benzodiazepine receptor-chloride ionophore complex (GABAA receptors) were examined in conjunction with allopregnanolone, the anti-conflict effects of allopregnanolone were effectively reversed only by the benzodiazepine receptor inverse agonist RO15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-α]-[1,4]benzodiazepine-3-carboxylate). Since this inverse agonist has been reported to inhibit the GABAA-activated chloride flux in neuronal membranes, it is likely that the stimulation of the chloride channel in GABAA receptors is an important component of the effects of allopregnanolone. In contrast, the benzodiazepine receptor antagonist flumazenil (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-α]-[1,4]benzodiazepine-3-carboxylate) did not block the anxiolytic-like actions of allopregnanolone, indicating that allopregnanolone does not bind at the benzodiazepine site directly. Isopropylbicyclophosphate, which binds at the picrotoxinin site on the GABAA receptors and blocks the behavioral actions of ethanol, also dose-dependently reversed the anti-conflict effect of this neurosteroid. The results suggest that allopregnanolone may be working either at a site specific for the benzodiazepine receptor inverse agonist RO15-4513 or at the picrotoxinin site to produce its potent anxiolytic-like behavioral effects. © 1997 Elsevier Science B.V.