PT  - JOURNAL ARTICLE
AU  - Kaminski, Rafal M.
AU  - Marini, Herbert
AU  - Ortinski, Pavel I.
AU  - Vicini, Stefano
AU  - Rogawski, Michael A.
TI  - The Pheromone Androstenol (5α-Androst-16-en-3α-ol) Is a Neurosteroid Positive Modulator of GABA<sub>A</sub> Receptors
AID  - 10.1124/jpet.105.098319
DP  - 2006 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 694--703
VI  - 317
IP  - 2
4099  - http://jpet.aspetjournals.org/content/317/2/694.short
4100  - http://jpet.aspetjournals.org/content/317/2/694.full
SO  - J Pharmacol Exp Ther2006 May 01; 317
AB  - 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 GABAA receptors. Here we show that androstenol has neurosteroid-like activity as a GABAA receptor modulator. In whole-cell recordings from cerebellar granule cells, androstenol (but not its 3β-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 α1β2γ2 and α2β2γ2 GABAA 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 3β-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 GABAA receptor modulator. GABAA 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 American Society for Pharmacology and Experimental Therapeutics