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

Abstract

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 (GABA A 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-4 H-imidazo [1,5-α]-[1,4]benzodiazepine-3-carboxylate). Since this inverse agonist has been reported to inhibit the GABA A-activated chloride flux in neuronal membranes, it is likely that the stimulation of the chloride channel in GABA A 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-4 H-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 GABA A 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.