Gunn et al. GABAA receptors, neurosteroids, and stress FIGURE 1 | A model for the regulation of neurosteroidogenesis. A diagrammatic representation of the pathways for the biosynthesis of 5α3α-THPROG from cholesterol. Receptors and signaling mechanisms potentially regulating steroidogenesis and sites of action of ligands used to target selective enzymatic pathways are additionally illustrated. In the proposed model, NMDA receptor activation may stimulate neurosteroidogenesis on a rapid time scale (Tokuda et al., 2011), possibly via the Ca2+ induced activation of nNOS and p38 MAPK (Izumi et al., 2008). In addition, glucocorticoids may regulate neurosteroidogenesis via rapid non-genomic effects through the activation of Gs-γβ, an effect that stimulates nNOS (Di et al., 2009). Furthermore, a number of stress-related neuropeptides (e.g., CRH, AVP), which are known to signal through Gs-coupled receptor complexes may modulate nNOS activity and thus inﬂuence neurosteroid synthesis. Receptors for these neuropeptides can additionally couple to Gq-proteins to raise intracellular Ca2+ levels and thus, couple to signaling cascades similar to those associated with NMDA receptor activation. These GPCR-dependent signaling pathways may provide a functional regulatory link between the stress axis and the de novo synthesis of 5α3α-THPROG. of an endogenous neurosteroid tone in these cells (Puia et al., 2003). In the hippocampus, CA1 pyramidal neurons are sensitive to physiologically signiﬁcant concentrations of 5α3α-THPROG (100 nM), while the same concentration of the neurosteroid has no effect upon inhibitory transmission in dentate gyrus gran- ule cells (DGGCs). However, the metabolically stable synthetic analog, ganaxolone, enhances inhibitory transmission at low con- centrations in CA1 neurons and DGGCs (Belelli and Herd, 2003). Interestingly, 3α-HSD, unlike 5α-reductase, is involved in both the synthesis and degradation of 5α3α-THPROG (and 5α3α- THDOC) as the cytosolic isoform catalyzes the reductive forma- tion of 5α3α-THPROG from 5α-dihydroprogesterone (5α-DHP), www.frontiersin.org December 2011 | Volume 5 | Article 131 | 3