PARTIAL AGONISM BY 3-ALPHA,21-DIHYDROXY-5-BETA-PREGNAN-20-ONE AT THE GAMMA-AMINOBUTYRIC-ACID, RECEPTOR NEUROSTEROID SITE

3 alpha,21-Dihydroxy-5 alpha-pregnan-20-one (5 alpha-THDOC) and 3 alph a-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) have full efficac y as allosteric modulators of [S-35]t-butylbicyclophosphorothionate ([ S-35]TBPS) binding to sites on the gamma-aminobutyric acid (GABA) type A receptor complex (GRC). Relative to 3 alpha,5 alpha-P and 5 alpha-T HDOC, 3 alpha,21-dihydroxy-5 beta-pregnan-20-one (5 beta-THDOC) has li mited efficacy as an allosteric modulator of [S-35]TBPS binding. Inter actions between 3 alpha,5 alpha-P, 5 alpha-THDOC and 5 beta-THDOC were examined to determine whether these neuroactive steroids share a comm on site for modulation of the GRC. The concentration-response curves f or both 3 alpha,5 alpha-P and 5 alpha-THDOC modulation of [S-35]TBPS b inding to brain and recombinantly derived GRCs are shifted rightward i n the presence of various concentrations of 5 beta-THDOC. Similarly, 5 beta-THDOC modulates GABA-evoked Cl- currents with low efficacy and i nhibits the potentiation of GABA-evoked Cl- currents by 3 alpha,5 alph a-P. Furthermore, behavioral studies reveal that 5 beta-THDOC antagoni zes 3 alpha,5 alpha-P-induced loss of the righting reflex in mice at a dose that has no effect alone. These results represent the first demo nstration of antagonist-like actions of a neuroactive steroid on the G RCs at levels ranging from the receptor to animal behavior and suggest the existence of partial agonist neurosteroids.