Abstract
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.
Footnotes
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Send reprint requests to: Kelvin W. Gee, Ph.D., Department of Pharmacology, College of Medicine, University of California, Irvine, Irvine, CA 92697.
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↵1 This work was supported by a grant from CoCensys, Inc.
- Abbreviations:
- 3α
- 5α-P, 3α-hydroxy-5α-pregnan-20-one
- GABA
- γ-aminobutyric acid
- GRC
- γ-aminobutyric type A receptor complex
- DMSO
- dimethylsulfoxide
- TBPS
- t-butylbicyclophosphorothionate
- 5α-THDOC
- 3α,21-dihydroxy-5α-pregnan-20-one
- 5β-THDOC
- 3α,21-dihydroxy-5β-pregnan-20-one
- LRR
- loss of the righting reflex
- ANOVA
- analysis of variance
- i.v.
- intravenous
- Received July 23, 1996.
- Accepted February 14, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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