Neurosteroids: Molecular mechanisms of action and psychopharmacological significance

In addition to the well-known genomic effects of steroid molecules via intracellular steroid receptors, certain steroids rapidly alter neuronal excitability through binding sites on neurotransmitter-gated ion channels. Several of these steroids accumulate in the brain after local synthesis or after metabolization of adrenal steroids. The 3α -hydroxy ring A-reduced pregnane steroids allopregnanolone and tetrahydrodeoxycorticosterone have been thought not to interact with intracellular receptors but enhance γ-aminobutyric acid (GABA)-mediated chloride currents. When administered systemically in the rat, these neurosteroids display anxiolytic and hypnotic activities that suggest pronounced systemic effects as well as a neuropsychopharmacological potential for modulation of sleep and anxiety. We demonstrated that these neurosteroids can regulate gene expression via the progesterone receptor. The induction of DNA-binding and transcriptional activation of the progesterone receptor requires intracellular oxidation of the neurosteroids into progesterone receptor-active 5α-pregnane steroids. Thus, in physiological concentrations these neurosteroids regulate neuronal function through their concurrent influence on transmitter-gated ion channels and gene expression. These findings extend the concept of a 'cross-talk' between membrane and nuclear hormone effects and provide a new role for the therapeutic application of these steroids in neurology and psychiatry.