Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior.

Area of Science:

• Neuroendocrinology
• Behavioral Neuroscience
• Pharmacology

Background:

• Anabolic-androgenic steroids (AAS) affect metabolism, sex drive, and mental acuity.
• AAS abuse is linked to irritability, aggression, and depression, but mechanisms are unclear.
• Neurosteroid biosynthesis is implicated in mood and behavior regulation.

Purpose of the Study:

• Investigate behavioral and neurochemical changes from long-term testosterone propionate (TP) administration.
• Examine the role of neurosteroids, specifically allopregnanolone (Allo), in TP-induced aggression.
• Determine if aggression and neurochemical changes can be reversed by modulating neurosteroid levels.

Main Methods:

• Protracted (3-week) administration of testosterone propionate (TP) to socially isolated and group-housed male and female mice.
• Measurement of aggression, brain neurosteroid content (allopregnanolone), and 5alpha-reductase type I mRNA expression.
• Restitution experiments with progesterone and estrogen; administration of S-norfluoxetine (S-NFLX).

Main Results:

• Male but not female socially isolated mice showed aggression linked to down-regulated neurosteroid biosynthesis.
• In female mice, TP induced aggression, decreased brain allopregnanolone (Allo), and reduced 5alpha-reductase type I mRNA.
• Progesterone and estrogen normalized Allo content and prevented aggression in spayed mice treated with TP.
• S-norfluoxetine (S-NFLX) increased brain Allo and abolished TP-induced aggression.

Conclusions:

• TP-induced aggression results from down-regulated neurosteroid biosynthesis.
• Restoring brain Allo content, via progesterone, estrogen, or S-NFLX, can reverse TP-induced aggression.
• Neurosteroids play a critical role in mediating the behavioral effects of anabolic steroids.