PT - JOURNAL ARTICLE AU - Bao G. Xue AU - Edward R. Whittemore AU - Chong H. Park AU - Richard M. Woodward AU - Nancy C. Lan AU - Kelvin W. Gee TI - Partial Agonism by 3α,21-Dihydroxy-5β-pregnan-20-one at the γ-Aminobutyric Acid<sub>A</sub> Receptor Neurosteroid Site DP - 1997 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1095--1101 VI - 281 IP - 3 4099 - http://jpet.aspetjournals.org/content/281/3/1095.short 4100 - http://jpet.aspetjournals.org/content/281/3/1095.full SO - J Pharmacol Exp Ther1997 Jun 01; 281 AB - 3α,21-Dihydroxy-5α-pregnan-20-one (5α-THDOC) and 3α-hydroxy-5α-pregnan-20-one (3α,5α-P) have full efficacy as allosteric modulators of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding to sites on the γ-aminobutyric acid (GABA) type A receptor complex (GRC). Relative to 3α,5α-P and 5α-THDOC, 3α,21-dihydroxy-5β-pregnan-20-one (5β-THDOC) has limited efficacy as an allosteric modulator of [35S]TBPS binding. Interactions between 3α,5α-P, 5α-THDOC and 5β-THDOC were examined to determine whether these neuroactive steroids share a common site for modulation of the GRC. The concentration-response curves for both 3α,5α-P and 5α-THDOC modulation of [35S]TBPS binding to brain and recombinantly derived GRCs are shifted rightward in the presence of various concentrations of 5β-THDOC. Similarly, 5β-THDOC modulates GABA-evoked Cl− currents with low efficacy and inhibits the potentiation of GABA-evoked Cl− currents by 3α,5α-P. Furthermore, behavioral studies reveal that 5β-THDOC antagonizes 3α,5α-P-induced loss of the righting reflex in mice at a dose that has no effect alone. These results represent the first demonstration of antagonist-like actions of a neuroactive steroid on the GRCs at levels ranging from the receptor to animal behavior and suggest the existence of partial agonist neurosteroids. The American Society for Pharmacology and Experimental Therapeutics