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 acid (FGIN-1-44) displaced [H-3]1-(2-chlorophenyl)-. N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide([H-3]PK 11195) and [H-3]4-chlorodiazepam ([H-3]4'CD) from binding sites located on the rat brain mitochondrial DBI receptor 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 ligand that does not possess steroidogenic activity. FGIN-1-27 and FGIN-1-44 failed to bind to other transmitter receptors, including gamma-aminobutyric(A) receptors. When administered orally to rats, both FGIN-1-27 and FGIN-1-44 reduced fear of novelty in the elevated plus maze test. 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 because of its greater bioavailability. FGIN-1-27 increased the brain pregnenolone content in adrenalectomized-castrated rats pretreated with trilostane (in order to prevent metabolism of pregnenolone to progesterone). This increase was blocked by pretreatment with PK 11195. Although FGIN-1-27 and FGIN-1-44 increased the corticosterone concentration in adrenal glands and plasma of hypophysectomized rats in a PK 11195-sensitive manner, both drugs failed to increase adrenal steroidogenesis in sham-operated rats. Because the PK 11195-sensitive antineophobic action of FGIN-1 derivatives was also apparent in adrenalectomized-castrated rats, we conclude that neurosteroids produced as a result of brain MDRC stimulation may contribute to the pharmacological actions of these drugs.