Regulation of Neurosteroid Biosynthesis. Brain Allo content but not that of its precursor progesterone is decreased after protracted administration of TP to female mice. Thus, a possible mechanism by which TP induces a brain Allo content decrease is a down-regulation of the expression of specific enzymes, i.e., 5α-RI or 3α-hydroxysteroid-oxidoreductase (3α-HSOR), which converts progesterone into 5α-dihydroprogesterone and Allo, respectively. In this study, we show that 5α-RI mRNA expression is decreased in brain tissue of aggressive male and female mice although it fails to decrease in brain tissue of mice that do not exhibit aggressive behavior. Studies by Torres and Ortega (42, 43) and by Torres et al . (44) have recently reported that protracted TP administration to rats results in a negative modulation of the expression of the gene encoding 5α-RI in brain, but not in peripheral tissues such as liver and prostate, where TP up-regulates the expression of 5α-RI mRNA. Because 5α-RI is the rate-limiting step enzyme in pregnane steroid metabolism (22, 28), these results suggest that the down-regulation of brain 5α-RI expression may be responsible for the decrease of brain Allo biosynthesis after TP administration. We cannot exclude, however, that, in addition to 5α-RI, 3α-HSOR also is down-regulated during TP treatment.
An alternative mechanism by which TP may cause a decrease of Allo brain content could be a competition between testosterone and progesterone in the catalytic action of 5α-RI (45). Thus, additional detailed time-course and dose-response studies are needed to precisely define the mechanisms by which testosterone induces brain Allo content decrease.
CONCLUSIONS
The neuronal mechanism underlying TP-induced aggression in female mice very likely is similar to that regulating aggression in untreated SI males. This mechanism involves the GABAergic system, which is positively and allosterically modulated by endogenous Allo (21-25, 46, 47). Thus, protracted exposure of rodents to TP may decrease GABAergic tone by reducing the bioavailability of pregnane steroids (by means of an inhibitory action on 5α-RI expression) that have a prominent endogenous regulatory role in the affinity of GABAA receptors for GABA. This action may mediate most of the behavioral abnormalities that are associated with AAS use and abuse.
Collectively, these findings suggest an important modulatory role for the endogenous pregnane steroids on GABAergic inhibitory synaptic transmission.
It is noteworthy that the pregnane-enhancing drug S-NFLX in submicromolar doses increases brain Allo content (19, 20, 22) and attenuates aggressive behavior in TP-treated mice. Likely, this observation may have important implications for designing future treatments for androgen abuse.