NEUROSTEROIDS - PHARMACOLOGICAL EFFECTS OF A 3-BETA-HYDROXY-STEROID DEHYDROGENASE INHIBITOR

Pregnenolone (PREG) is synthesized and accumulated in rodent brain, independently of the presence of adrenals and gonads. Trilostane, a competitive inhibitor of the Delta 5-3 beta-hydroxysteroid dehydrogenase Delta 5-->4 isomerase (3 beta-HSD) isoenzymes, prevents the further metabolism of PREG, and is likely to increase its concentration and those of its far, acid (L) and sulfate esters (S) in brain, PREG S is a GABA antagonist and might regulate particular types of aggressive behavior. Intact and castrated adrenalectomized adult male rats were treated with Trilostane. In operated rats, the brain, contrary to plasma, still contained sizable amounts of PREG and of progesterone (PROC). Trilostane decreased significantly the concentration of PROC and increased that of PREG in accordance with a substrate-to-product relationship, thus confirming that both compounds are 'neurosteroids'. The concentrations of corticosterone in adrenals and plasma of Trilostane-treated intact rats were unchanged, as a consequence of a feed-back ACTH hypersecretion. Inhibition of 3 beta-HSD activity was indicated by large increases of PREG in adrenals, plasma and brain. PREG S was itself increased in brain. However, ACTH hypersecretion also provoked significant increases of PROC and of its neu reactive metabolite 3 alpha-hydroxy-5 alpha-pregnan-20-one in adrenals, plasma, and brain.