We examined the effects of the neurosteroid pregnenolone sulfate (PS) on GA
BA(A) receptor-mediated synaptic currents and currents elicited by rapid ap
plications of GABA onto nucleated outside-out patches in cultured postnatal
rat hippocampal neurons. At 10 mu M, PS significantly depressed peak respo
nses and accelerated the decay of evoked inhibitory synaptic currents.
In nucleated outside-out patches, PS depressed peak currents and speeded de
activation after 5 msec applications of a saturating concentration of GABA.
PS also increased the rate and degree of macroscopic GABA receptor desensi
tization during prolonged GABA applications. In a paired GABA application p
aradigm, PS slowed the rate of recovery from desensitization.
In contrast to its prominent effects on currents produced by saturating GAB
A concentrations, PS had only small effects on peak currents and failed to
alter deactivation after brief applications of the weakly desensitizing GAB
A(A) receptor agonists taurine and beta-alanine. However, when beta-alanine
was applied for a sufficient duration to promote receptor desensitization,
PS augmented macroscopic desensitization and slowed deactivation.
These results suggest that PS inhibits GABA-gated chloride currents by enha
ncing receptor desensitization and stabilizing desensitized states. This co
ntention is supported by kinetic modeling studies in which increases in the
rate of entry into doubly liganded desensitized states mimic most effects
of PS.