Abstract
The progesterone metabolites allopregnanolone (Allo, 3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (Preg, 3alpha-hydroxy-5beta-pregnan-20-one) enhance the gamma-aminobutyric acid (GABA) action through a distinct site on the GABAA-receptor. Their 3beta-isomers epiallopregnanolone (Epiallo, 3beta-hydroxy-5alpha-pregnan-20-one) and epipregnanolone (Epipreg, 3beta-hydroxy-5beta-pregnan-20-one), do not have these effects on GABAA-receptors. We have studied the interaction between Allo/Preg and their 3beta-isomers on action potentials in rat hippocampal slices in vitro. The Schaffer collaterals were stimulated electrically in CA1 striatum radiatum and the population spike (POPSP) was recorded in stratum pyramidale. A 0.5-nL droplet of drug was applied locally onto stratum oriens-pyramidale via a pressure pipett. Muscimol (Mus) (12.5 fmol), Allo and Preg (6.25 fmol) caused a reversible inhibition of POPSP. On the other hand, 6.25 fmol Epiallo had no significant effect on POPSP compared with the vehicle control. Combined Epiallo and Allo application caused a dose-dependent reduction of the Allo inhibition of POPSP. A full blockage was seen at a molar ratio of 1:1. Epiallo also blocked the Preg inhibition of POPSP, when the two drugs were combined in a molar ratio of 1:1. Epiallo did not block the Mus inhibition of POPSP, when the two drugs were combined at a molar ratio of 1:2. Bath perfusion of 12.5 microM Epiallo blocked the inhibition of 6.25 fmol Allo on POPSP, but not the inhibition caused by 12.5 fmol Mus. Epipreg did not block the inhibition of Allo and Preg on POPSP, when it was combined with the two latter drugs at a molar ratio of 1:1. Our data suggest that the steroid modulation of the GABAA transmitted inhibition of the CA1 pyramidal neurones is selectively and dose dependently blocked by Epiallo, the 3beta-hydroxy-isomer of Allo, but not by Epipreg, the 3beta-hydroxy-isomer of Preg.
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