COMPARATIVE MODULATION BY 3-ALPHA,5-ALPHA AND 3-BETA,5-BETA NEUROSTEROIDS OF GABA BINDING-SITES DURING AVIAN CENTRAL-NERVOUS-SYSTEM DEVELOPMENT

Neurosteroids are endogenous Central Nervous System (CNS) compounds wh ich act mainly by allosteric modulation of the GABA(A) receptor comple x. The presence of a 3 alpha-hydroxyl group and a 5 alpha-hydrogen ato m have been found to be essential structural requirements for biologic al activity in mammals. In the present work we report the enhancing ac tivity on [H-3]GABA binding to its receptor sites in chick optic lobe produced by progesterone metabolites 3 alpha-hydroxy,5 alpha-gregnan-2 0-one (3 alpha,5 alpha-P) and 3 beta-hydroxy,5 beta-pregnan-20-one (3 beta,5 beta-P). Both steroids were found able to enhance [H-3]GABA bin ding along ontogeny, displaying a similar profile at early development al stages, while in adulthood 3 alpha,5 alpha-P had greater potency (E C50 0.22 mu M) and enhancing effect (E-max: 122%). In adult synaptic m embranes, the two compounds displayed a complex interaction with the G ABA(A) receptor, disclosed by a Schild plot with slope below one and a n incomplete displacement of 3 alpha,5 alpha-P by its 3 beta,5 beta is omer. Such complexity could be related to the steroidogenic profile in avian CNS, with 5 beta-reduced progesterone metabolites present since early development, while 3 alpha,5 alpha-P is found only in adulthood . Bearing in mind differences between avian and mammalian steroidogeni c profiles and the relevance of 5 beta-steroids in early avian develop ment, we propose that 3 beta,5 beta-P, instead of the classical potent 3 alpha,5 alpha-steroids, may be the endogenous modulator of GABAergi c activity in developing avian brain.