Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior

Abstract

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.

Fig. 1.

Time course of aggressiveness development in male (A and B) and female (C and D) mice caged in SI (A and C) or GH (B and D). Aggressive behavior of a resident mouse against a same-sex (A and B) or a male bulbectomized (C and D) intruder was measured as the duration of attacks (sec.) in a 10-min exposure. TP (0.5 mg/kg s.c.) or vehicle were administered once daily. The resident-intruder test was performed 24 h after the last dose of TP. Each value is the mean ± SEM of six to eight animals. *, P < 0.05; **, P < 0.01 when the duration of attacks at a given time period is compared with period 0-week; †, P < 0.05; ††, P < 0.05 when the duration of attacks is compared with sham-operated plus TP group (one-way ANOVA followed by Dunnett's test).

Fig. 2.

Duration of attacks toward a male bulbectomized intruder (A) and OB Allo content (B) in 3-week SI sham-operated or spayed mice. TP (0.5 mg/kg s.c., once daily) and hormone-restitution with progesterone (1 mg/kg s.c., once daily) and estradiol (0.05 mg/kg s.c., once daily) were administered for 3 weeks during SI. Each value is the mean ± SEM of six animals. *, P < 0.05; **, P < 0.01 when compared with spayed plus TP group (one-way ANOVA followed by Dunnett's test).

Fig. 3.

S-NFLX reduces aggression in spayed or sham-operated SI mice. Each value is the mean ± SEM of four mice. S-NFLX (1.8 μmol/kg, i.p.) was given 30 min before resident-intruder tests. *, P < 0.01 when S-NFLX-treated groups are compared with respective control groups (one-way ANOVA followed by Dunnett's test).