Interactions of the neurosteroid dehydroepiandrosterone sulfate with the GABA(A) receptor complex reveals that it may act via the picrotoxin site.

The interactions of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were investigated with various binding sites of the gamma-aminobutyric acid (GABA(A)) receptor complex to rat brain membranes, and on GABA-induced [36Cl-] influx in mammalian cortical cultured neurons. DHEAS and DHEA did not affect the binding of [3H]flunitrazepam to the benzodiazepine binding sites. In contrast, DHEAS, but not DHEA, inhibited the binding of [3H]GABA and [35S]TBPS to rat brain cerebral cortical and cerebellar membranes in a concentration-dependent manner. DHEAS decreased the Bmax values of both the high and low affinity GABA receptor binding sites without affecting their affinity constants. In contrast, DHEAS inhibited [35S]TBPS binding competitively, as analyzed by Scatchard analysis. In dissociation kinetic studies, DHEAS dissociated [35S]TBPS from rat cerebral cortical membranes in a monophasic pattern that was similar to that observed with inhibitors of GABA(A) receptors such as TBPS and picrotoxin but different from pentobarbital and GABA. Taken together, these results suggest that DHEAS binds to the TBPS/picrotoxin site of the GABA(A) receptor complex, and this interaction may be responsible for the noncompetitive inhibition of GABA responses observed with DHEAS. Furthermore, we confirmed that DHEAS inhibits GABA responses, as measured by GABA-induced [36Cl-] influx in cultured cortical neurons. Studies with DHEA indicate that this neurosteroid does not interact with the GABA(A) receptor complex.