Androstenol (5α-androst-16-en-3α-ol) Is a Novel Neurosteroid Positive Modulator of GABAA Receptors: In Vitro and In Vivo Studies

Abstract

Androstenol (5α-androst-16-en-3α-ol) is a volatile steroid compound belonging to the group of 16-androstenes found in human plasma. It is structurally similar to endogenous A-ring reduced steroids that act as positive modulators of GABA_A receptors, i.e., neurosteroids. Thus, we have hypothesized that androstenol may have electrophysiological and behavioral traits characteristic for neurosteroids.

The influence of androstenol on GABA_A receptors currents under voltage clamp conditions in mouse cerebellar granule cell cultures, rat brain slices, and HEK cells expressing human GABA_A receptor subunits has been assessed. Additionally, the effect of androstenol on 4-aminopyridine–induced epileptiform activity in rat hippocampal slices was studied. Assessment of anticonvulsant, anxiolytic, and antidepressant effects of androstenol in the 6 Hz, PTZ, open field, and forced swim models has also been performed.

We have found that androstenol potentiates GABA-evoked currents in HEK cells as well as in cerebellar cultures and slices. Androstenol inhibited epileptiform activity induced by 4-aminopyridine in rat brain slices and had strong anticonvulsant effects against PTZ- and 6 Hz-induced seizures in mice. In addition, we have found that androstenol has anxiolytic and antidepressant effects in animal models.

These results for the first time demonstrate that androstenol acts as a positive modulator of GABA_A receptors and has behavioral properties compatible with this physiological action. Androstenol may act as an endogenous modulator of GABA_A receptors, and it may be useful in treatment of epilepsy and possibly other neurological disorders, i.e., anxiety and depression.