GABA-active steroids: endogenous modulators of GABA-gated chloride ion conductance.

Naturally occurring 3-alpha-hydroxy ring A-reduced metabolites of progesterone and deoxycorticosterone and their synthetic analogues bind to specific sites within the hydrophobic channel domain of the GABAA receptor complex. Acting at these sites, these ligands function as positive allosteric effectors of the complex; they potentiate GABA-stimulated membrane chloride ion conductance, enhance the binding of [3H]muscimol and [3H]flunitrazepam, and displace the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS), a channel ligand that is a specific marker of the GABA-associated chloride ionophore. Moreover, steroid metabolites (namely pregnenolone sulfate and dehydroepiandrosterone sulfate) have been identified that display properties of GABA-negative allosteric effectors. The identification of this membrane-associated steroid binding should stimulate development of new classes of anxiolytic, sedative-hypnotic, anticonvulsant, anesthetic, and muscle-relaxant medications that may be devoid of many of the side effects associated with benzodiazepines and barbiturates. Also, elucidation of the physiologic role of this binding site should contribute both to our understanding of endogenous mechanisms for modulating inhibitory neurotransmission, and the pathophysiologic role of the GABAA receptor complex in a variety of neuropsychiatric disorders.