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NEUROPHARMACOLOGY

The Pheromone Androstenol (5-Androst-16-en-3-ol) Is a Neurosteroid Positive Modulator of GABA_A Receptors

Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.M.K., H.M., M.A.R.); and Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, District of Columbia (P.I.O., S.V.)

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 3-epimer) caused a concentration-dependent enhancement of GABA-activated currents (EC₅₀, 0.4 µM in cultures; 1.4 µM in slices) and prolonged the duration of spontaneous and miniature inhibitory postsynaptic currents. Androstenol (0.1–1 µM) also potentiated the amplitude of GABA-activated currents in human embryonic kidney 293 cells transfected with recombinant 122 and 222 GABA_A receptors and, at high concentrations (10–300 µM), 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 3-epimer, conferred seizure protection in the 6-Hz electroshock and pentylenetetrazol models (ED₅₀ 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.

Address correspondence to: Dr. Michael A. Rogawski, Epilepsy Research Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 35, Room 1C-1002, MSC 3702, 35 Convent Drive, Bethesda, MD 20892-3702. E-mail: michael.rogawski{at}nih.gov