The pheromone androstenol (5α-androst-16-en-3α-ol) is a neurosteroid positive modulator of GABAa receptors

Rafal M. Kaminski, Herbert Marini, Pavel I. Ortinski, Stefano Vicini, Michael A Rogawski

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)694-703
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume317
Issue number2
DOIs
StatePublished - May 2006
Externally publishedYes

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Androstenols
Pheromones
GABA-A Receptors
Neurotransmitter Agents
gamma-Aminobutyric Acid
Electroshock
Inhibitory Postsynaptic Potentials
Pentylenetetrazole
Volatilization
Anti-Anxiety Agents
Patch-Clamp Techniques
Antidepressive Agents
Testis
Seizures
Animal Models
androst-16-en-3-ol
Kidney

ASJC Scopus subject areas

  • Pharmacology

Cite this

The pheromone androstenol (5α-androst-16-en-3α-ol) is a neurosteroid positive modulator of GABAa receptors. / Kaminski, Rafal M.; Marini, Herbert; Ortinski, Pavel I.; Vicini, Stefano; Rogawski, Michael A.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 317, No. 2, 05.2006, p. 694-703.

Research output: Contribution to journalArticle

Kaminski, Rafal M. ; Marini, Herbert ; Ortinski, Pavel I. ; Vicini, Stefano ; Rogawski, Michael A. / The pheromone androstenol (5α-androst-16-en-3α-ol) is a neurosteroid positive modulator of GABAa receptors. In: Journal of Pharmacology and Experimental Therapeutics. 2006 ; Vol. 317, No. 2. pp. 694-703.
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