In addition to an action on metabolism, anabolic/androgenic steroids also increase sex drive and mental acuity. If abused, such steroids can cause irritability, impulsive aggression, and signs of major depression [Pearson, H. (2004) Nature 431, 500-501], but the mechanisms that produce these symptoms are unknown. The present study investigates behavioral and neurochemical alterations occurring in association with protracted (3-week) administration of testosterone propionate (TP) to socially isolated (SI) and group-housed male and female mice. Male but not female SI mice exhibit aggression that correlates with the down-regulation of brain neurosteroid biosynthesis. However, in female mice, long-term TP administration induces aggression associated with a decrease of brain allopregnanolone (Allo) content and a decrease (approximately 40%) of 5alpha-reductase type I mRNA expression. In spayed mice treated with TP, restitution experiments with progesterone and estrogen normalize brain Allo content and prevent aggression. Submicromolar doses of S-norfluoxetine (S-NFLX) that are insufficient to inhibit serotonin reuptake selectively increase brain Allo content and abolish TP-induced aggression. Our results support the view that TP-induced aggressive behavior is the result of a TP-mediated neurosteroid biosynthesis down-regulation that can be reversed by the S-NFLX-induced increase of brain Allo content.