STIMULATION OF BRAIN STEROIDOGENESIS BY 2-ARYL-INDOLE-3-ACETAMIDE DERIVATIVES ACTING AT THE MITOCHONDRIAL DIAZEPAM-BINDING INHIBITOR RECEPTOR COMPLEX

The 2-aryl-indole-3-acetamide derivatives, 2-hexyl-indole-3-acetamide (FGIN-1-27) and 2-hexyl-indole-3-acetamide-N-benzene-tricarboxylic aci d (FGIN-1-44) displaced [H-3]1-(2-chlorophenyl)-. 1-methylpropyl)-3-is oquinoline-carboxamide([H-3]PK 11195) and [H-3]4-chlorodiazepam ([H-3] 4'CD) from binding sites located on the rat brain mitochondrial DBI re ceptor complex (MDRC) with K(i) values in the nanomolar range. Both 2- aryl-indole-3-acetamide derivatives acted as agonists at the MDRC and thereby stimulated the rate of pregnenolone synthesis in isolated rat brain mitochondria; this effect was inhibited by PK 11195, an MDRC lig and that does not possess steroidogenic activity. FGIN-1-27 and FGIN-1 -44 failed to bind to other transmitter receptors, including gamma-ami nobutyric(A) receptors. When administered orally to rats, both FGIN-1- 27 and FGIN-1-44 reduced fear of novelty in the elevated plus maze tes t. This action was prevented by PK 11195, but not by flumazenil. FGIN- 1-44, which was rapidly converted to FGIN-1-27 in the rat brain, was 3 to 4 times more potent than FGIN-1-27 in reducing fear of novelty bec ause of its greater bioavailability. FGIN-1-27 increased the brain pre gnenolone content in adrenalectomized-castrated rats pretreated with t rilostane (in order to prevent metabolism of pregnenolone to progester one). This increase was blocked by pretreatment with PK 11195. Althoug h FGIN-1-27 and FGIN-1-44 increased the corticosterone concentration i n adrenal glands and plasma of hypophysectomized rats in a PK 11195-se nsitive manner, both drugs failed to increase adrenal steroidogenesis in sham-operated rats. Because the PK 11195-sensitive antineophobic ac tion of FGIN-1 derivatives was also apparent in adrenalectomized-castr ated rats, we conclude that neurosteroids produced as a result of brai n MDRC stimulation may contribute to the pharmacological actions of th ese drugs.