Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior.
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.
Pinna
Graziano
G
Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, Chicago, IL 60612, USA. gpinna@psych.uic.edu
Costa
Erminio
E
Guidotti
Alessandro
A
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000374:Aggression / Q000502:physiology*; D000818:Animals; D001519:Behavior / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D009919:Orchiectomy; D010052:Ovariectomy; D011280:Pregnanolone / Q000096:biosynthesis* / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis* / Q000494:pharmacology
D004967:Estrogens; D011963:Receptors, GABA-A; D005473:Fluoxetine; D013739:Testosterone; D011374:Progesterone; D011280:Pregnanolone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C036139:norfluoxetine