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 neuro nal excitability through binding sites on neurotransmitter-gated ion c hannels. Several of these steroids accumulate in the brain after local synthesis or after metabolization of adrenal steroids. The 3 alpha-hy droxy ring A-reduced pregnane steroids allopregnanolone and tetrahydro deoxycorticosterone have been thought not to interact with intracellul ar receptors but enhance gamma-aminobutyric acid (GABA)-mediated chlor ide currents. When administered systemically in the rat, these neurost eroids display anxiolytic and hypnotic activities that suggest pronoun ced systemic effects as well as a neuropsychopharmacological potential for modulation of sleep and anxiety. We demonstrated that these neuro steroids can regulate gene expression via the progesterone receptor. T he induction of DNA-binding and transcriptional activation of the prog esterone receptor requires intracellular oxidation of the neurosteroid s into progesterone receptor-active Sa-pregnane steroids. Thus, in phy siological concentrations these neurosteroids regulate neuronal functi on through their concurrent influence on transmitter-gated ion channel s 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 an d psychiatry.