5-BETA-PREGNAN-3-BETA-OL-20-ONE, A SPECIFIC ANTAGONIST AT THE NEUROSTEROID SITE OF THE GABA-A RECEPTOR-COMPLEX

Studies were made on the potentiation of [H-3]flunitrazepam binding to rat brain membranes by gamma-aminobutyric acid (GABA), pentobarbitone and pregnanolone (5-beta-pregnan-3-alpha-ol-20-one). Epipregnanolone, the 3-beta isomer of pregnanolone, inhibited competitively the potentiation by pregnanolone with a K(i) of 10.5-mu-M without affecting that of GABA. The potentiation by pentobarbitone was slightly enhanced. Epipregnanolone alone showed only slight potentiation of benzodiazepine binding. These findings demonstrate that epipregnanolone is a specific antagonist of the neurosteroid site of the GABA(A) receptor and raise the possibility of a physiological role for 3-beta-hydroxysteroids in modulating this receptor.