BIOSYNTHESIS OF PROGESTERONE DERIVED NEUROSTEROIDS BY DEVELOPING AVIAN CNS - IN-VITRO EFFECTS ON THE GABA(A) RECEPTOR COMPLEX

It has been demonstrated in different vertebrate species that the GABA (A) receptor complex is modulated by certain steroids. Theses results prompted work on the synthesis of these neurosteroids in the Central N ervous System. However, there are scarcely any studies analyzing their production or their modulatory effects on this receptor during develo pment. In this work, the biosynthesis of [C-14]progesterone metabolite s as weil as the characterization of their in vitro effects on the GAB A, receptor complex in developing chick optic lobe were investigated. Studies on progesterone metabolism indicated that this steroid was con verted to 5 beta-pregnanedione, 5 beta-pregan-3 beta-ol-20-one. and a 20-hydroxy derivative. Radio-active progesterone was completely metabo lized at early embryonic stages, and a great proportion of 5 beta-preg nanedione was converted to 5 beta-pregnan-3 beta-ol-20-one. Thus, it s eems that some of the steroidogenic activities present in chick optic lobe are age-dependent, though greater at embryonic stages. Results fr om ill vitro modulation of [H-3]flunitrazepam binding by 5 beta-preena n-3 beta-ol-20-one indicated that this steroid produces a one-componen t-concentration dependent enhancement above control binding. 5 beta-pr egnan-3 beta-ol-20-one EC50 values were 0.195 +/- 0.049, 0.101 +/- 0.0 17, 0.147 +/- 0.009, and 0.569 +/- 0.114 mu M, and E-max were 22.37 +/ - 1.57, 23.67 +/- 4.02, 29.01 +/- 1.08, and 15.11 +/- 2.67% at embryon ic days 11, 14, hatching, and postnatal day 21, respectively. In concl usion, the biosynthesis of 5 beta-pregnan-3 beta-ol-20-one from proges terone in developing chick optic lobe. together with its ability to mo dulate the GABA(A) receptor present in such tissues, suggests a physio logical role of this neurosteroid in developing avian Central Nervous System. (C) 1998 ISDN. Published by Elsevier Science Ltd.