3-BETA-OH-5-BETA-PREGNAN-20-ONE ENHANCES [H-3] GABA BINDING IN DEVELOPING CHICK OPTIC LOBE

The neurosteroids are synthesized in the CNS and act mainly through al losteric modulation of the GABA(A) receptor. Structure-activity relati onship studies in mammalian CNS have shown that a 3 alpha-hydroxyl gro up and a 5 alpha-reduced A-ring are striking features for their biolog ical activity, while the 3 beta, 5 beta structures as in 3 beta, 5 bet a-P are completely inactive. In this work we report the enhancing acti vity of epipregnanolone on [H-3]GABA binding to its receptor sites in the chick optic lobe. Concentration-effect curves for this neurosteroi d showed a concentration dependent activity with different potencies a t 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 t his steroid behaved as a partial agonist of the steroid recognition si te. Considering the developmental profile for steroidogenesis in avian tissues and the biological relevance of 5 beta-reduced steroids in ea rly development, we propose that 3 or its 3 alpha-epimer, pregnanolone , instead of the potent 3 alpha, 5 alpha neurosteroids, modulates GABA (A) receptors in the chick optic lobe during development.