Testosterone's analgesic, anxiolytic, and cognitive-enhancing effects may be due in part to actions of its 5alpha-reduced metabolites in the hippocampus.

Although testosterone (T) may decrease anxiety and enhance cognitive performance, its mechanisms are not well understood. The authors hypothesized that if T's effects are mediated in part through actions of its 5alpha-reduced, nonaromatizable metabolite dihydrotestosterone (DHT) and/or its 3alpha-hydroxysteroid dehydrogenase reduced metabolite 3alpha-androstanediol (3alpha-diol) in the hippocampus, then T, DHT, and 3alpha-diol administration should produce similar behavioral effects concomitant with elevating T metabolites in the hippocampus. Gonadectomized male rats administered T, DHT, or 3alpha-diol via Silastic capsules or intrahippocampal infusions had greater analgesia (tail flick, paw lick), less anxiety behavior (plus-maze, open field, defensive freezing), and better learning (inhibitory avoidance) compared with vehicle control rats. Only 3alpha-diol levels in the hippocampus were consistently elevated in conjunction with these behavioral effects.