Pregnane neurosteroids exert opposite effects on GABA and glycine-induced chloride current in isolated rat neurons

The ability of endogenous neurosteroids (NSs) with pregnane skeleton modified at positions C-3 and C-5 to modulate the functional activity of inhibitory glycine receptors (GlyR) and ionotropic ɣ-aminobutyric acid receptors (GABA_A R) was estimated. The glycine and GABA-induced chloride current (I_Gly and I_GABA ) were measured in isolated pyramidal neurons of the rat hippocampus and in isolated rat cerebellar Purkinje cells, respectively. Our experiments demonstrated that pregnane NSs affected I_GABA and I_Gly in a different manner. At low concentrations (up to 5 μM), tested pregnane NSs increased or did not change the peak amplitude of the I_GABA , but reduced the I_Gly by decreasing the peak amplitude and/or accelerating desensitization. Namely, allopregnanolone (ALLO), epipregnanolone (EPI), pregnanolone (PA), pregnanolone sulfate (PAS) and 5β-dihydroprogesterone (5β-DHP) enhanced the I_GABA in Purkinje cells. Dose-response curves plotted in the concentration range from 1 nM to 100 μM were smooth for EPI and 5β-DHP, but bell-shaped for ALLO, PA and PAS. The peak amplitude of the I_Gly was reduced by PA, PAS, and 5α- and 5β-DHP. In contrast, ALLO, ISO and EPI did not modulate it. Dose-response curves for the inhibition of the I_Gly peak amplitude were smooth for all active compounds. All NSs accelerated desensitization of the I_Gly . The dose-response relationship for this effect was smooth for ALLO, PA, PAS and 5β-DHP, but it was U-shaped for EPI, 5α-DHP and ISO. These results, together with our previous results on NSs with androstane skeleton, offer comprehensive overview for understanding the mechanisms of effects of NSs on I_Gly and I_GABA .