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

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 3␤-epimer) caused a concentration-dependent enhancement of GABA-activated currents (EC 50 , 0.4 M in cultures; 1.4 M in slices) and prolonged the duration of spontaneous and miniature inhibitory postsynaptic currents. Androstenol (0.1-1 M) also potentiated the amplitude of GABA-activated currents in human embryonic kidney 293 cells transfected with recombinant ␣1␤2␥2 and ␣2␤2␥2 GABA A receptors and, at high concentrations (10 -300 M), 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 (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 Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABAA Receptors

“…Although we did not estimate the subunit composition of GABA A receptors in adult CA1 pyramidal neurons used in the study, GABA A receptors composed of the ␣1␤2␥2-and ␣2␤2␥2-subunits are abundant subunit combinations in the CA1 region, whereas the neurosteroid-sensitive ␣1␤2␦-subunit composition is generally present in the dentate granule cells. Androstenol, an androstanediol-like steroid, had comparable efficacy in potentiating GABA currents in human embryonic kidney-293 cells transfected with ␣1␤2␥2 or ␣2␤2␥2-subunit isoforms to that obtained with native receptors in hippocampus neurons (Kaminski et al, 2006). Because ␦-subunit-containing receptors are not usually present in the adult CA1 pyramidal cells used in the present study, the effect of androstanediol on such receptors isoforms expressed in granule cells remains to be determined in future studies.…”

Recent developments in the significance and therapeutic relevance of neuroactive steroids — Introduction to the special issue

“…1996; Park-Chung et al, 1999;Kaminski et al, 2005) and testosterone (Kaminski et al, 2005;Kaminski et al, 2006) enhance GABAergic neurotransmission and produce inhibitory neurobehavioral effects such as anxiolytic, anticonvulsant and sedative actions. The excitatory neuroactive steroids include the sulfated derivatives of pregnenolone and DHEA (Farb and Gibbs, 1996) as well as the 3α,5α-and 3α,5β-reduced metabolites of cortisol (Penland and Morrow, 2004).…”

17β-Nitro-5α-androstan-3α-ol and its 3β-methyl derivative: Neurosteroid analogs with potent anticonvulsant and anxiolytic activities

“…Anxiolytic activity was assessed with the elevated zero maze as described (Kaminski et al, 2006). The maze (Hamilton-Kinder, Poway, CA) was positioned in the center of a room under dim lighting.…”

“…In addition, the synthetic 17β-carbonitrile (Hawkinson et al, 1994) and 17β-epoxide (Anderson et al, 2000) analogs exhibit similar GABA A receptor modulatory potency and efficacy as allopregnanolone (Wittmer et al, 1996). Interestingly, the natural (16–17 unsaturated) pheromone, 3α-androstenol, lacks a 17-position substituent yet retains GABA A receptor modulating activity, albeit of reduced potency (Kaminski et al, 2006). Here we show that the 3α-hydroxy-17β-nitro analog ( 2b ) and its 3β-methyl derivative ( 2c ) influence radioligand binding at GABA A receptors with potency similar to allopregnanolone and exhibit potent anticonvulsant and anxiolytic-like activity in mouse models.…”