| Title: | The pheromone androstenol (5 alpha-androst-16-en-3 alpha-ol) is a neurosteroid positive modulator of GABAA receptors |
| Author(s): | Kaminski RM; Marini H; Ortinski PI; Vicini S; Rogawski MA; |
| Address: | "Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA" |
| ISSN/ISBN: | 0022-3565 (Print) 0022-3565 (Linking) |
| Abstract: | "Androstenol is a steroidal compound belonging to the group of odorous 16-androstenes, first isolated from boar testes and also found in humans. Androstenol has pheromone-like properties in both animals and humans, but the molecular targets of its pheromonal activity are unknown. Androstenol is structurally similar to endogenous A-ring reduced neurosteroids that act as positive modulators of GABA(A) receptors. Here we show that androstenol has neurosteroid-like activity as a GABA(A) receptor modulator. In whole-cell recordings from cerebellar granule cells, androstenol (but not its 3beta-epimer) caused a concentration-dependent enhancement of GABA-activated currents (EC(50), 0.4 microM in cultures; 1.4 microM in slices) and prolonged the duration of spontaneous and miniature inhibitory postsynaptic currents. Androstenol (0.1-1 microM) also potentiated the amplitude of GABA-activated currents in human embryonic kidney 293 cells transfected with recombinant alpha1beta2gamma2 and alpha2beta2gamma2 GABA(A) receptors and, at high concentrations (10-300 microM), directly activated currents in these cells. Systemic administration of androstenol (30-50 mg/kg) caused anxiolytic-like effects in mice in the open-field test and elevated zero-maze and antidepressant-like effects in the forced swim test (5-10 mg/kg). Androstenol, but not its 3beta-epimer, conferred seizure protection in the 6-Hz electroshock and pentylenetetrazol models (ED(50) values, 21.9 and 48.9 mg/kg, respectively). The various actions of androstenol in the whole-animal models are consistent with its activity as a GABA(A) receptor modulator. GABA(A) receptors could represent a target for androstenol as a pheromone, for which it is well suited because of high volatility and lipophilicity, or as a conventional hormonal neurosteroid" |
| Keywords: | "Androstenols/*pharmacology Animals Behavior, Animal/*drug effects Cell Line Cerebellum/drug effects/metabolism Dose-Response Relationship, Drug GABA Modulators/*pharmacology Humans Male Mice Mice, Inbred Strains Molecular Structure Pheromones/*pharmacolog;" |
| Notes: | "MedlineKaminski, Rafal M Marini, Herbert Ortinski, Pavel I Vicini, Stefano Rogawski, Michael A eng MH-64797/MH/NIMH NIH HHS/ Intramural NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural 2006/01/18 J Pharmacol Exp Ther. 2006 May; 317(2):694-703. doi: 10.1124/jpet.105.098319. Epub 2006 Jan 13" |
