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.

The Pheromone Androstenol (5alpha-Androst-16-en-3alpha-ol) is aNeurosteroid Positive Modulator of GABAA Receptors

MARINI, Herbert Ryan;
2006-01-01

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.
2006
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11570/1673910
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