The octadecaneuropeptide ODN stimulates neurosteroid biosynthesis through activation of central-type benzodiazepine receptors

Neurosteroids may play a major role in the regulation of various neurophysi ological and behavioural processes. However, while the biochemical pathways involved in the synthesis of neuroactive steroids in the central nervous s ystem are now elucidated, the mechanisms controlling the activity of neuros teroid-producing cells remain almost completely unknown. In the present stu dy, we have investigated the effect of the octadecaneuropeptide (ODN), an e ndogenous ligand of benzodiazepine receptors, in the control of steroid bio synthesis in the frog hypothalamus. Glial cells containing ODN-like immunor eactivity were found to send their thick processes in the close vicinity of neurones expressing the steroidogenic enzyme 3 beta -hydroxysteroid dehydr ogenase. Exposure of frog hypothalamic explants to graded concentrations of ODN (10(-10)-10(-5) M) produced a dose-dependent increase in the conversio n of tritiated pregnenolone into various radioactive steroids, including 17 -hydroxypregnenolone, progesterone, 17-hydroxyprogesterone, dehydroepiandro sterone and dihydrotestosterone. The ODN-induced stimulation of neurosteroi d biosynthesis was mimicked by the central-type benzodiazepine receptor (CB R) inverse agonists methyl beta -carboline-3-carboxylate (beta -CCM) and me thyl 6,7-dimethoxy-4-ethyl-beta -carboline-3-carboxylate (DMCM). The stimul atory effects of ODN, beta -CCM and DMCM on steroid formation was markedly reduced by the CBR antagonist flumazenil. The ODN-evoked stimulation of neu rosteroid production was also significantly attenuated by GABA. Collectivel y, these data indicate that the endozepine ODN, released by glial cell proc esses in the vicinity of 3 beta -hydroxysteroid dehydrogenase-containing ne urones, stimulates the biosynthesis of neurosteroids through activation of central-type benzodiazepines receptors.