5 alpha-pregnan-3 alpha,20 alpha-diol behaves like a partial agonist in the modulation of GABA-stimulated chloride ion uptake by synaptoneurosomes.
In rat cortical synaptoneurosomes, the maximum potentiation of GABA-stimulated 36Cl uptake produced by 5 alpha-pregnan-3 alpha,20 alpha-diol (5 alpha-pregnanediol) is significantly less than that elicited by 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha-OH-DHP). This observation suggests that 5 alpha-pregnanediol may be a partial agonist whereas 3 alpha-OH-DHP acts as a full agonist at a common site on or near the GABAA/benzodiazepine receptor-chloride ionophore complex (GBRC). This hypothesis is supported by the finding that 5 alpha-pregnanediol will antagonize in a dose-dependent manner the enhancement of GABA-stimulated 36Cl uptake produced by 3 alpha-OH-DHP under certain conditions. Collectively, these findings support the hypothesis that GBRC-active progesterone metabolites with varying degrees of efficacy exist as reflected by their differential ability to potentiate 36Cl uptake in brain synaptoneurosomes.
Belelli
D
D
Division of Biological Sciences, School of Pharmacy, University of Southern California, Los Angeles 90033.
Gee
K W
KW
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D002998:Clonazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007476:Ionophores / Q000378:metabolism*; D011276:Pregnanediol / Q000494:pharmacology*; D011280:Pregnanolone / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D002712:Chlorides; C062606:GABA-benzodiazepine receptor-chloride ionophore complex; D007476:Ionophores; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam; D011280:Pregnanolone; D011276:Pregnanediol; D001640:Bicuculline