Testosterone's Anti-anxiety and Analgesic Effects May Be Due in Part to Actions of Its 5alpha-reduced Metabolites in the Hippocampus

Although testosterone (T) may have effects to enhance analgesia and reduce anxiety, its effects and mechanisms are not well understood. We hypothesized that if T's anti-anxiety and analgesic effects are due in part to actions of its 5alpha-reduced metabolite (dihydrotestosterone-DHT) and/or its 3alpha-hydroxysteroid dehydrogenase reduced metabolite (3alpha-androstanediol-3alpha-diol), in the hippocampus, then androgen regimens that increase levels of these metabolites in the hippocampus should produce anti-anxiety behavior, and analgesic effects, in gonadectomized (GDX) male rats. In Experiment 1, GDX rats were administered T, DHT, 3alpha-diol (1 mg/kg, SC), or vehicle. In Experiment 2, GDX rats had T, DHT, 3alpha-diol-containing inserts, or empty control inserts applied to the dorsal hippocampus immediately prior to behavioral testing. Androgen-administered rats (SC or intrahippocampal) showed significantly more exploratory behavior in the open field and elevated plus maze, less freezing in response to shock, and longer tailflick and pawlick latencies. These findings suggest that T's anti-anxiety effects may be due in part to actions of its 5alpha-reduced metabolites in the dorsal hippocampus.