Vol. 281, Issue 3, 1095-1101, 1997

Partial Agonism by 3,21-Dihydroxy-5-pregnan-20-one at the -Aminobutyric Acid_A Receptor Neurosteroid Site¹

Bao G. Xue, Edward R. Whittemore, Chong H. Park, Richard M. Woodward, Nancy C. Lan and Kelvin W. Gee

Department of Pharmacology (B.G.X., C.H.P., K.W.G.), College of Medicine, University of California, Irvine, California, and CoCensys, Inc. (E.R.W., R.M.W., N.C.L.), Irvine, California

3,21-Dihydroxy-5-pregnan-20-one (5-THDOC) and 3-hydroxy-5-pregnan-20-one (3,5-P) have full efficacy as allosteric modulators of [³⁵S]t-butylbicyclophosphorothionate ([³⁵S]TBPS) binding to sites on the -aminobutyric acid (GABA) type A receptor complex (GRC). Relative to 3,5-P and 5-THDOC, 3,21-dihydroxy-5-pregnan-20-one (5-THDOC) has limited efficacy as an allosteric modulator of [³⁵S]TBPS binding. Interactions between 3,5-P, 5-THDOC and 5-THDOC were examined to determine whether these neuroactive steroids share a common site for modulation of the GRC. The concentration-response curves for both 3,5-P and 5-THDOC modulation of [³⁵S]TBPS binding to brain and recombinantly derived GRCs are shifted rightward in the presence of various concentrations of 5-THDOC. Similarly, 5-THDOC modulates GABA-evoked Cl currents with low efficacy and inhibits the potentiation of GABA-evoked Cl currents by 3,5-P. Furthermore, behavioral studies reveal that 5-THDOC antagonizes 3,5-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.