Metabolites of the steroid hormone progesterone are potent positive GABA-A receptor modulators. All steroids with hormonal activity except estradiol have similar chemical structure in the A-ring with a ketone in the 3-position and they are mainly metabolized to 3alpha-OH-steroids. Many of these steroids have GABA-A receptor modulatory effects. GABA-A receptor modulators are known to disturb memory and learning including the progesterone metabolite allopregnanolone (Johansson et al 2002). We have newly shown that allopregnanolone in low stress levels given continuously during 3 months permanently give enhanced learning and memory deterioration in transgenic Alzheimer mice (Bengtsson et al 2012). In humans chronic treatment with Medroxy-progesterone-acetate (MPA) during 5 years doubles the frequency of dementia (Shumacher et al 2003). We have now synthesized and investigated the effect of MPA and 4 of its 3alpha-OH metabolites. Patch-clamp methods were used in recombinant HEK-cells expressing alpha5beta3gamma2L and alpha1beta2gamma2L GABA-A receptors. Neither MPA nor any of its 4, 3alpha- OH metabolites had any activity on the alpha1beta2gamma2L receptor. However, MPA itself had a strong positive allosteric effect on the alpha5beta3gamma2L GABA-A receptor. MPA had also a direct effect on baseline shift and open the chloride ion channel by itself. The 3alpha-OH, 5alpha/beta-MPA or 3beta-OH, 5alpha/beta-MPA were not active neither as agonists nor antagonists on the alpha5beta3gamma2L receptor. Johansson M, Birzniece V, Lindblad C, Olsson T, BäckströmT. 2002. Brain Res 934,125–131, Bengtsson S, Johansson M, Bäckström T, Wang M. Journal of Alzheimer's Disease. 2012. E-publ. Shumaker SA. et al. 2003. JAMA 289, 2651–2662