Neurosteroids in the mouse brain : Behavioral and pharmacological effects of a 3β-hydroxysteroid dehydrogenase inhibitor

Abstract Inhibition of the aggressive behavior of castrated male mice toward lactating female intruders by dehydroepiandrosterone (DHEA) is correlated with a decrease of pregnenolone sulfate (PREG S) concentrations in brain. We attempted to establish a cause to effect relationship by preventing the decrease of PREG S with trilostane (TRIL), a competitive inhibitor of Δ5-3β-hydroxysteroid dehydrogenase Δ5 → 4 isomerase enzyme. Indeed, TRIL elicited a large increase of PREG levels in brain. Those of PREG S were, however, unchanged, and TRIL unexpectedly decreased the aggressive behavior of control castrated males and did not counteract the inhibition elicited by DHEA. The neurosedative progesterone (PROG) metabolite, 3α-hydroxy-5α-pregnan-20-one (TH PROG), undetectable in the brain of control mice, reached nanomolar concentration range in TRIL-treated ones. However, injection of appropriate amounts of PROG, producing an even larger increase of brain TH PROG, had no antiaggressive effect. Finally, the latter was attributed to the large (up to 80 nM) TRIL-induced increase of brain 3α,21-dihydroxy-5α-pregnan-20-one, which like TH PROG potentiates inhibitory γ-aminobutyric acid (GABA)ergic neurotransmission.