GABA-A receptor (GABA-A-R) agonistic modulators e.g. benzodiazepines, barbiturates and alcohol, used chronically give permanent memory and learning impairment, and increased risk for dementia. The progesterone metabolite allopregnanolone (ALLO) is a GABA-A-R agonist (GABA-steroid) and impairs learning in rats in the Morris Water Maze. In humans medroxy- progesterone doubles the dementia frequency in 5 years. Chronic stress, burnout-syndrome and adrenal steroids are linked to development of dementia, especially Alzheimer type. During stress a high number of steroid hormones are produced. They are metabolized to 3a-OH- 5a-reduced steroids several being modulators of the GABA-A-R function. Pregnane steroids with 3-bhydroxy-configuration (3b-steroids) have been shown to reduce the ALLO enhanced GABA effect. The aim of our studies has been to investigate the mechanism of the agonistic effect by ALLO and the antagonistic effect by 3b-steroids. The 3b- isomer of ALLO reduced the efficacy of ALLO in a non-competitive way. Further, 3b-steroids increased the desensitization rate of current response. By the [³⁵S]TBPS-binding assay it is possible to study the agonistic effect of ALLO but not the antagonistic effect of the 3b-isomer of ALLO. The mechanism of the 3b-steroid is therefore suggested being desensitization dependent in contrast to ALLO, which has been suggested to decrease the GABA unbinding rate. The knowledge that diversity of endogenous steroids interact with the GABA-A-R function is of importance for further understanding of different sex and stress steroid related symptoms and disorders.