Neuropsychopharmacological properties of neuroactive steroids

In addition to the well-known genomic effects of steroid molecules via intr acellular steroid receptors, certain steroids rapidly alter neuronal excita bility through interaction with neurotransmitter-gated ion channels. Severa l of these steroids accumulate in the brain after local synthesis or after metabolism of adrenal steroids. The 3 alpha-hydroxy ring A-reduced pregnane steroids allopregnanolone and tetrahydrodeoxycorticosterone have been thou ght not to interact with intracellular receptors, but enhance gamma-aminobu tyric acid (GABA)-mediated chloride currents, whereas pregnenolone sulfate and dehydroepiandrosterone (DHEA) sulfate display functional antagonistic p roperties at GABA(A) receptors. We demonstrated that these neuroactive ster oids can regulate also gene expression via the progesterone receptor after intracellular oxidation. Thus, in physiological concentrations these neuroa ctive steroids regulate neuronal function through their concurrent influenc e on transmitter-gated ion channels and gene expression. When administered in animal studies, memory-enhancing effects have been shown for pregnenolon e sulfate and DHEA. The 3 alpha-hydroxy ring A-reduced neuroactive steroids predominantly display anxiolytic, anticonvulsant, and hypnotic activities. Sleep studies evaluating the effects of progesterone as a precursor molecu le for these neuroactive steroids revealed a sleep electroencephalogram pat tern similar to that obtained by the administration of benzodiazepines. The se findings extend the concept of a "cross-talk" between membrane and nucle ar hormone effects and provide a new role for the therapeutic application o f these steroids in neurology and psychiatry. (C) 1999 Elsevier Science Inc . All rights reserved.