Most of the actions of neurosteroids on the central nervous system are mediated through allosteric modulation of the ␥-aminobutyric acid type A (GABA A) receptor, but a direct effect of GABA on the regulation of neurosteroid biosynthesis has never been investigated. In the present report, we have attempted to determine whether 3-hydroxysteroid dehydrogenase (3-HSD)-containing neurons, which secrete neurosteroids in the frog hypothalamus, also express the GABAA receptor, and we have investigated the effect of GABA on neurosteroid biosynthesis by frog hypothalamic explants. Double immunohistochemical labeling revealed that most 3-HSD-positive neurons also contain GABAA receptor ␣3 and 2͞3 subunit-like immunoreactivities. Pulse-chase experiments showed that GABA inhibited in a dose-dependent manner the conversion of tritiated pregnenolone into radioactive steroids, including 17-hydroxy-pregnenolone, progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone, and dihydrotestosterone. The effect of GABA on neurosteroid biosynthesis was mimicked by the GABA A receptor agonist muscimol but was not affected by the GABA B receptor agonist baclofen. The selective GABAA receptor antagonists bicuculline and SR95531 reversed the inhibitory effect of GABA on neurosteroid formation. The present results indicate that steroid-producing neurons of the frog hypothalamus express the GABAA receptor ␣3 and 2͞3 subunits. Our data also demonstrate that GABA, acting on GABA A receptors at the hypothalamic level, inhibits the activity of several key steroidogenic enzymes, including 3-HSD and cytochrome P450C17 (17␣-hydroxylase).neuroactive steroids ͉ 3-hydroxysteroid dehydrogenase ͉ GABA A-benzodiazepine receptor complex
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