It is puzzling why an increase in allopregnanolone during the menstrual cycle is related to development of negative mood as allopregnanolone should be anxiolytic agent like benzodiazepines. However, earlier reports from human and animal models also indicated that all GABAA-receptor agonists could induce negative symptoms with anxiety, irritability/aggressiveness in certain individuals. GABA-steroids are anti-epileptic (Backstrom et al., 1984; Landgren et al., 1987) and in animal experiments they also possess an anxiolytic effect similar to benzodiazepines (Wieland et al., 1991). On the other hand, elevated testosterone in men may increase their generosity, primarily to attract a potential mate. Testosterone levels play a major role in risk-taking during financial decisions. Men who produce more testosterone are more likely to engage in extramarital sex. Men who produce less testosterone are more likely to be in a relationship or married, and men who produce more testosterone are more likely to divorce. However, the testosterone changes observed do not seem to be maintained as relationships develop over time. There has been speculation that these changes in testosterone result in the temporary reduction of differences in behavior between the sexes. There is a time lag effect when testosterone is administered, on genital arousal in women. Recently, it has been shown that the α5 subunit is important for sedative tolerance development to benzodiazepines and for acquisition and expression of associative memory and spatial learning (Collinson et al., 2002; Crestani et al., 2002; van Rijnsoever et al., 2004; Yee et al., 2004). The α6β2/3γ2, α6β2/3δ, and α6β2/3γ2 receptors are found mainly in the cerebellum and dorsal cochlear nucleus (Fritschy and Brunig, 2003). The α1β2γ2 receptor is present in most brain areas and it is localized to interneurons in the hippocampus and cortex (layer I–IV), and cerebral Purkinje cells (McKernan and Whiting, 1996). Receptors containing the α4-, α5-, and α6-subnit, as well as the β1-, γ1–3, δ-, π-, and θ-subunit, form a minor receptor population. It appears that neurosteroids more or less exclusively target the GABAA-receptor which is a ligand gated anion-selective channel (Schofield et al., 1987). Given the γ-subunit have little or no effect on the maximal GABA-modulation effect of allopregnanolone, it significantly influences the potency of the steroid with "physiological concentrations" (3–30 nM; Belelli et al., 2002). In fact, the efficacy of allopregnanolone action at the binary α1β1 receptor is higher than that at the ternary α1β1γ2 receptors (Maitra and Reynolds, 1999; Belelli et al., 2002). Likewise, the subtypes of the β-subunit (β1–3) have little action on the effects of neurosteroids (Hadingham et al., 1993; Sanna et al., 1997; Belelli et al., 2002). The effect of neurosteroids on the GABAA-receptor can be attributable to variations in the receptor subunit composition. Such an increase in frequency is due to the presynaptic effect of neurosteroids (Poisbeau et al., 1997; Haage et al., 2002) by a mechanism that involves altered presynaptic Ca2+ permeability and activation of presynaptic GABAA-receptors. The high sensitivity of neurosteroids in extrasynaptic receptor may represent an important target for neurosteroids. On the other hand, the tonic conductance of hippocampal CA1 neurons expressing GABAA-receptor with α5 subunit is affected by 3α5α-THDOC (≥100 nM; Stell et al., 2003; Belelli and Lambert, 2005; Farrant and Nusser, 2005). Extrasynaptic receptors exhibit both a high GABA affinity and reduced receptor desensitization in the continued presence of the agonist (Fritschy and Brunig, 2003).
