title: Partial agonism by 3alpha,21-dihydroxy-5beta-pregnan-20-one at the gamma-aminobutyric acidA receptor neurosteroid site.
abstract: 3alpha,21-Dihydroxy-5alpha-pregnan-20-one (5alpha-THDOC) and 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-P) have full efficacy as allosteric modulators of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding to sites on the gamma-aminobutyric acid (GABA) type A receptor complex (GRC). Relative to 3alpha,5alpha-P and 5alpha-THDOC, 3alpha,21-dihydroxy-5beta-pregnan-20-one (5beta-THDOC) has limited efficacy as an allosteric modulator of [35S]TBPS binding. Interactions between 3alpha,5alpha-P, 5alpha-THDOC and 5beta-THDOC were examined to determine whether these neuroactive steroids share a common site for modulation of the GRC. The concentration-response curves for both 3alpha,5alpha-P and 5alpha-THDOC modulation of [35S]TBPS binding to brain and recombinantly derived GRCs are shifted rightward in the presence of various concentrations of 5beta-THDOC. Similarly, 5beta-THDOC modulates GABA-evoked Cl- currents with low efficacy and inhibits the potentiation of GABA-evoked Cl- currents by 3alpha,5alpha-P. Furthermore, behavioral studies reveal that 5beta-THDOC antagonizes 3alpha,5alpha-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.
authors.affiliation: Department of Pharmacology, College of Medicine, University of California, Irvine 92697, USA.
authors.forename: B G
authors.initials: BG
authors.lastname: Xue
authors.forename: E R
authors.initials: ER
authors.lastname: Whittemore
authors.forename: C H
authors.initials: CH
authors.lastname: Park
authors.forename: R M
authors.initials: RM
authors.lastname: Woodward
authors.forename: N C
authors.initials: NC
authors.lastname: Lan
authors.forename: K W
authors.initials: KW
authors.lastname: Gee
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects*; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D013256:Steroids / Q000494:pharmacology*
chemical_list: D014151:Anti-Anxiety Agents; D011963:Receptors, GABA-A; D013256:Steroids; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone