The inhibitory effects of allopregnanolone and pregnanolone on the population spike, evoked in the rat hippocampal CA1 stratum pyramidale in vitro, can be blocked selectively by epiallopregnanolone

The progesterone metabolites allopregnanolone (Allo, 3 alpha-hydroxy-5 alph a-pregnan-20-one) and pregnanolone (Preg, 3 alpha-hydroxy-5 beta-pregnan-20 -one) enhance the gamma-aminobutyric acid (GABA) action through a distinct site on the GABA(A)-receptor. Their 3 beta-isomers epiallopregnanolone (Epi allo, 3 beta-hydroxy-5 alpha-pregnan-20-one) and epipregnanolone (Epipreg, 3 beta-hydroxy-5 beta-pregnan-20-one), do not have these effects on GABA(A) -receptors. We have studied the interaction between Allo/Preg and their 3 b eta-isomers on action potentials in rat hippocampal slices in vitro. The Sc haffer collaterals were stimulated electrically in CA1 striatum radiatum an d 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 p ressure pipett. Muscimol (Mus) (12.5 fmol), Allo and Preg (6.25 fmol) cause d a reversible inhibition of POPSP. On the other hand, 6.25 fmol Epiallo ha d no significant effect on POPSP compared with the vehicle control. Combine d Epiallo and Allo application caused a dose-dependent reduction of the All o inhibition of POPSP. A full blockage was seen at a molar ratio of 1:1. Ep iallo also blocked the Preg inhibition of POPSP, when the two drugs were co mbined 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 perf usion of 12.5 mu M Epiallo blocked the inhibition of 6.25 fmol Allo on POPS P, but not the inhibition caused by 12.5 fmol Mus. Epipreg did not block th e inhibition of Allo and Preg on POPSP, when it was combined with the two l atter drugs at a molar ratio of 1:1. Our data suggest that the steroid modu lation of the GABA(A) transmitted inhibition of the CA1 pyramidal neurones is selectively and dose dependently blocked by Epiallo, the 3 beta-hydroxy- isomer of Allo, but not by Epipreg, the 3 beta-hydroxy-isomer of Preg.