3 beta-OH-5 beta-pregnan-20-one enhances [3H]GABA binding in developing chick optic lobe

The neurosteroids are synthesized in the CNS and act mainly through allosteric modulation of the GABAA receptor. Structure-activity relationship studies in mammalian CNS have shown that a 3 alpha-hydroxyl group and a 5 alpha-reduced A-ring are striking features for their biological activity, while the 3 beta,5 beta structures as in 3 beta,5 beta-P are completely inactive. In this work we report the enhancing activity of epipregnanolone on [3H]GABA binding to its receptor sites in the chick optic lobe. Concentration-effect curves for this neurosteroid showed a concentration-dependent activity with different potencies at the three developmental stages studied, the hatching stage being the most sensitive to the steroid stimulatory effect. The displacement of a potent 3 alpha,5 alpha steroid by epipregnanolone indicated that this steroid behaved as a partial agonist of the steroid recognition site. Considering the developmental profile for steroidogenesis in avian tissues and the biological relevance of 5 beta-reduced steroids in early development, we propose that 3 or its 3 alpha-epimer, pregnanolone, instead of the potent 3 alpha,5 alpha neurosteroids, modulates GABAA receptors in the chick optic lobe during development.