Evidence that 3 alpha-hydroxy-5 alpha-pregnan-20-one is a physiologically relevant modulator of GABA-ergic neurotransmission.
3 alpha-Hydroxy-5 alpha-pregnan-20-one (HPO) is a progesterone metabolite which exhibits narcotic properties at high concentrations by interactions with the receptor for gamma-aminobutyric acid (GABA). The present investigation characterized low-dose effects of HPO on GABAA receptor binding, by determining the allosteric properties of HPO on the in vitro binding of 3H-muscimol to membrane fractions from the cerebella of ovariectomized rats. A newly developed method for tissue preparation was used to wash out endogenous ligands interfering with the assay. HPO reduced the affinity of 3H-muscimol to GABAA receptor sites by 52% and enhanced the number of accessible binding sites from 5.5 +/- 0.5 to 7.5 +/- 1.3 pmol/mg protein at subnanomolar (0.1 nM) HPO concentrations. The modulatory effects of HPO on GABAA receptor binding provide evidence that this pregnane steroid might be a physiologically relevant modulator of GABAergic neurotransmission.
Hiemke
C
C
Department of Psychiatry, University of Mainz, Germany.
Jussofie
A
A
Jüptner
M
M
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002531:Cerebellum / Q000378:metabolism / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D005260:Female; D009118:Muscimol / Q000378:metabolism; D010052:Ovariectomy; D011280:Pregnanolone / Q000502:physiology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014316:Tritium
D011963:Receptors, GABA-A; D014316:Tritium; D009118:Muscimol; D011280:Pregnanolone