The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABAA Receptors

Testosterone modulates seizure susceptibility, but the underlying mechanisms are obscure. Recently, we demonstrated that testosterone affects seizure activity via its conversion to neuro-steroids in the brain. Androstanediol (5 alpha-androstan-3 alpha,17 beta-diol) is an endogenous neurosteroid synthesized from testosterone. However, the molecular mechanism underlying the seizure protection activity of androstanediol remains unclear. Here, we show that androstanediol has positive allosteric activity as a GABA A receptor modulator. In whole-cell recordings from acutely dissociated hippocampus CA1 pyramidal cells, androstanediol (but not its 3 beta-epimer) produced a concentration-dependent enhancement of GABA-activated currents (EC50 of 5 mu M). At 1 mu M, androstanediol produced a 50% potentiation of GABA responses. In the absence of GABA, androstanediol has moderate direct effects on GABA A receptor-mediated currents at high concentrations. Systemic doses of androstanediol (5-100 mg/kg), but not its 3 beta-epimer, caused dose-dependent suppression of behavioral and electrographic seizures in mouse hippocampus kindling, which is a model of temporal lobe epilepsy. The ED50 value for antiseizure effects of androstanediol was 50 mg/ kg, which did not produce sedation/motor toxicity. At high (2X ED50) doses, androstanediol produced complete seizure protection that lasted for up to 3 h after injection. The estimated plasma concentrations of androstanediol producing 50% seizure protection in the kindling model (10.6 mu M) are within the range of concentrations that modulate GABA A receptors. These studies suggest that androstanediol could be a neurosteroid mediator of testosterone actions on neuronal excitability and seizure susceptibility via its activity as a GABA A receptor modulator and that androstanediol may play a key role in men with epilepsy, especially during the age-related decline in androgen levels.