Testosterone's metabolism in the hippocampus may mediate its anti-anxiety effects in male rats.

Androgens may mediate anxiety behaviors; however, these effects and mechanisms of androgens are not well understood. The following experiments investigated whether testosterone (T)'s effects on anxiety behavior are mediated by its 5alpha-reduced, nonaromatizable metabolite dihydrotestosterone (DHT) and/or its 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) reduced metabolite 3alpha-androstanediol (3alpha-diol). In Experiment 1, gonadally-intact adult male rats and gonadectomized (GDX), DHT-replaced rats had similar low levels of anxiety behavior in the open field and elevated plus maze and fear behavior in the defensive freezing task compared with GDX control rats. In Experiment 2, intact or DHT-replaced rats that received blank inserts to the hippocampus demonstrated less anxiety behavior than did rats administered an implant of indomethacin, a 3alpha-HSD inhibitor, to the dorsal hippocampus. These data indicate that T's 5alpha-reduced metabolite, DHT, can reduce anxiety behavior and that blocking metabolism to 3alpha-diol in the hippocampus can attenuate these effects.