Systemic doses of androstanediol (5–100 mg/kg), but not its 3β-epimer, caused dose-dependent suppression of behavioral and electrographic seizures in mouse hippocampus kindling, which is a model of temporal lobe epilepsy. In whole-cell recordings from acutely dissociated hippocampus CA1 pyramidal cells, androstanediol (but not its 3β-epimer) produced a concentration-dependent enhancement of GABA-activated currents (EC50 of 5 μM). However, the molecular mechanism underlying the seizure protection activity of androstanediol remains unclear. Androstanediol (5α-androstan-3α,17β-diol) is an endogenous neurosteroid synthesized from testosterone. However, it was not fully excluded that a more complicated model of a multivalent interaction between hydrophobic steroids and receptor is employed. Obviously, 5α-pregnan-3β, 20α-diol and 5β-pregnan-3β, 20β-diol prolonged the fast offset time course of GABA response, suggesting that the inherent association between 3β-OH steroids and receptor has rather high affinity. In a receptor complex with reduced desensitization components to GABA-activation (e.g., mutant receptors), the PS-inhibition was also greatly reduced (Akk et al., 2001). The inhibition of metabolism can greatly enhance the response of the tonic current in dentate granule cells to endogenous neurosteroids, but not on the synthetic metabolically stable ganaxalone (Belelli and Herd, 2003). Tonic inhibition is reduced in the δ-subunit "knockout" mice, and the residual tonic current was insensitive to 3α5α-THDOC (Mihalek et al., 1999; Stell et al., 2003). At low "physiological" concentrations (10–100 nM), 3α5α-THDOC selectively enhance the tonic conductance, with little or no effect on the phasic conductance in mouse DGCs and CGCs (Stell et al., 2003; Belelli and Lambert, 2005; Farrant and Nusser, 2005). Moreover, in the preoptic cells in the hypothalamus, 100 nM allopregnanolone prolong the spontaneous current (Haage et al., 2005; Stromberg et al., 2006). On the other hand, micromolar concentrations are required to produce equivalent responses in oxytocin neurons of hypothalamus (Brussaard et al., 1997; Koksma et al., 2003). Here, we show that androstanediol has positive allosteric activity as a GABAA receptor modulator. Some authors have reported a significant increase in serum LH level accompanied by a decrease in testosterone level of rats exposed to ELF-EMFs (17, 18). At the end of 1 week no significant change was observed in testosterone level;however, this parameter was decreased significantly at the end of the second week as compared to sham exposed rats. Al-Akhras et al. exposed rats to 50 Hz, 25 µT ELF-EMF for 18 weeks and observed a significant decrease in serum testosterone level of rats only after 6 and 12 weeks of exposure (17). In the present study, exposure of animals to 50 Hz, 0.5 mT ELF-EMF for 30 days had no appreciable effect on testosterone level as compared to sham exposed animals, although a slight decrease was observed. Bicuculline methiodidedid not appreciably affect testosterone level in our study, although a slight increase was observed when high dose of bicuculline was administered (23). A small portion of approximately 3% of testosterone is reversibly converted in the liver into androstenedione by 17β-HSD. Subsequently, 3α-androstanediol and 3α-etiocholanediol are converted by 17β-HSD into androsterone and etiocholanolone, which is followed by their conjugation and excretion. Then, 5α-DHT and 5β-DHT are converted by 3α-HSD into 3α-androstanediol and 3α-etiocholanediol, respectively. In the hepatic 17-ketosteroid pathway of testosterone metabolism, testosterone is converted in the liver by 5α-reductase and 5β-reductase into 5α-DHT and the inactive 5β-DHT, respectively. The conjugates of testosterone and its hepatic metabolites are released from the liver into circulation and excreted in the urine and bile. Androsterone and etiocholanolone are then glucuronidated and to a lesser extent sulfated similarly to testosterone. Approximately 50% of testosterone is metabolized via conjugation into testosterone glucuronide and to a lesser extent testosterone sulfate by glucuronosyltransferases and sulfotransferases, respectively. These investigators convincingly argued that the relative mRNA abundance of GABAA receptor subunits would be a mechanism that ensured proportional abundance of protein. We show that the impulsivity response may be GABAA subunit-specific when involving supraphysiological concentrations of testosterone. Altogether, this is the first GABAA and GABAB subunit gene expression analysis in an animal model of testosterone-induced impulsivity. Although the relationship of GABAA receptors and CaMKIV is not well established, a histochemical study shows CaMKIV is expressed in a subgroup of GABAergic neurons in all layers of cortical interneurons of adult monkey area V1 in which parvalbumin was present (Lalonde et al., 2004). It has also been reported that CaMKII activation can lead to an increase in specific GABA receptor subunits (Churn et al., 2002). Thus, the possibility of HPA axis-responsive genes and changes in specific subunits of GABA by testosterone cannot be ruled out. Neurosteroids may both enhance and inhibit GABAergic neurotransmission (Wang et al., 2002; Mennerick et al., 2004; Rahman et al., 2006; Stromberg et al., 2006). However, the potency and efficacy effect of 3α-androstane steroid is lower than those of 3α-pregnan steroids (Rahman et al., 2006). The efficacy of 3β5β-P to inhibit GABAA-receptor is significantly different from 3β5α-P (Rahman et al., 2006; Wang et al., 2007). Studies with 3α5α-THDOC and its stereoisomer 3α5β-THDOC revealed important differences in potency, efficacy, and regional selectivity at the GABAA-receptor in favor of 5α-reduction (Gee and Lan, 1991; Mennerick et al., 2004). Allopregnanolone with 5α-reduction is generally more potent than its 5β-isomer, pregnanolone, as GABAA-receptor agonist both in vivo and in vitro. Even if steroids with either 5α or 5β conformations are active, spatial difference in this position may affect the pharmacology of the neurosteroids. However men with high testosterone were significantly 27% less generous in an ultimatum game. Test subjects with an artificially enhanced testosterone level generally made better, fairer offers than those who received placebos, thus reducing the risk of a rejection of their offer to a minimum. For one study, subjects took part in a behavioral experiment where the distribution of a real amount of money was decided. In humans, testosterone appears more to promote status-seeking and social dominance than simply increasing physical aggression. Thus the link between testosterone and aggression and violence is due to these being rewarded with social status. Moreover, the conversion of testosterone to estradiol regulates male aggression in sparrows during breeding season. The rise in testosterone during competition predicted aggression in males, but not in females.
