THE PHARMACOLOGY OF NEUROSTEROIDOGENESIS

In adrenal cortex and other steroidogenic tissues including glial cell s, the conversion of cholesterol into pregnenolone is catalyzed by the cytochrome P450(sec) located in the inner mitochondrial membrane. A c omplex mechanism operative in regulating cholesterol access to P450(se c) limits the rate of pregnenolone biosynthesis. Participating in this mechanism are DBI (diazepam binding inhibitor), an endogenous peptide that is highly expressed in steroidogenic cells and some of the DBI p rocessing products including DBI 17-50 (TTN). DBI and TTN activate ste roidogenesis by binding to a specific receptor located in the outer mi tochondrial membrane, termed mitochondrial DBI receptor complex (MDRC) . MDRC is a hetero-oligometric protein: only the subunit that includes the DBI and benzodiazepine (BZD) recognition sites has been cloned. S everal 2-aryl-3-indoleacetamide derivatives (FGIN-1-X) with highly sel ective affinity (nM) for MDRC were synthesized which can stimulate ste roidogenesis in mitochondrial preparations. These compounds stimulate adrenal cortex steroidogenesis in hypophysectomized rats but not in in tact animals. Moreover, this steroidogenesis in inhibited by the isoqu inoline carboxamide derivative PK 11195, a specific high affinity liga nd for MDRC with a low intrinsic steroidogenic activity. Some of the F GIN-1-X derivatives stimulate brain pregnenolone accumulation in adren alectomized-castrated rats. The FGIN-1-X derivatives that increase bra in pregnenolone content, elicit antineophobic activity and antagonize punished behavior in the Vogel conflict test in rats. These actions of FGIN-1-X are resistant to inhibition by flumazenil, a specific inhibi tor of BZD action in GABAA receptors but are antagonized by PK 11195, a specific blocker of the steroidogenesis activation via MDRC stimulat ion. It is postulated that the pharmacological action of FGIN-1-X depe nds on a positive modulation of the GABA action on GABA(A) receptors m ediated by the stimulation of brain neurosteroid production.