REVIEW ARTICLE published: 05 December 2011 doi: 10.3389/fnins.2011.00131 Neurosteroids and GABAA receptor interactions: a focus on stress Benjamin G. Gunn, Adam R. Brown, Jeremy J. Lambert and Delia Belelli * Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Ninewells Hospital, University of Dundee, Dundee, UK Edited by: Kazuyoshi Tsutsui, Waseda University, Japan Reviewed by: Michael Schumacher, INSERM, France Rainer Rupprecht, University Regensburg, Germany *Correspondence: Delia Belelli, Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK. e-mail: d.belelli@dundee.ac.uk Since the pioneering discovery of the rapid CNS depressant actions of steroids by the “father of stress,” Hans Seyle 70 years ago, brain-derived “neurosteroids” have emerged as powerful endogenous modulators of neuronal excitability. The majority of the interven- ing research has focused on a class of naturally occurring steroids that are metabolites of progesterone and deoxycorticosterone, which act in a non-genomic manner to selectively augment signals mediated by the main inhibitory receptor in the CNS, the GABAA receptor. Abnormal levels of such neurosteroids associate with a variety of neurological and psychi- atric disorders, suggesting that they serve important physiological and pathophysiological roles. A compelling case can be made to implicate neurosteroids in stress-related distur- bances. Here we will critically appraise how brain-derived neurosteroids may impact on the stress response to acute and chronic challenges, both pre- and postnatally through to adulthood. The pathological implications of such actions in the development of psy- chiatric disturbances will be discussed, with an emphasis on the therapeutic potential of neurosteroids for the treatment of stress-associated disorders. Keywords: synaptic inhibition, allopregnanolone, HPA axis, anxiety, maternal care INTRODUCTION In the 1940s, the Hungarian endocrinologist, Dr. Hans Selye demonstrated that certain pregnane steroids could induce sedation and anesthesia on a relatively rapid time scale, a property which precludes a genomic action (Selye, 1941). The molecular mech- anism underlying the rapid depressant action of these pregnane steroids remained unknown until the early 1980s, when Harrison and Simmonds (1984) demonstrated that a structurally related synthetic steroidal anesthetic, alphaxalone (5α-pregnane-3α-ol- 11,20-dione), potently enhanced GABAA receptor (GABAAR) function (a receptor for the main inhibitory neurotransmitter in the CNS) in a brain slice preparation. Subsequent studies revealed that certain endogenously synthesized steroids, such as the prog- esterone (PROG) metabolites 5α-pregnan-3α-ol-20-one (5α3α- THPROG), 5β-pregnan-3α-ol-20-one (5β3α-THPROG), and the deoxycorticosterone (DOC) metabolite 5α-pregnan-3α,21-diol- 20-one (5α3α-THDOC), were similarly potent (10–100 nM) posi- tive allosteric modulators of GABAAR function (Barker et al., 1987; Callachan et al., 1987; Gee et al., 1987, 1988; Harrison et al., 1987; Lambert et al., 1987, 2009; Peters et al., 1988). Indeed, the observed enhancement of GABAAR function by such steroids was consistent with their behavioral actions (anxiolytic, anticonvulsant, sedative, analgesic, and anesthetic; Lambert et al., 1995; Gasior et al., 1999; Rupprecht, 2003). The subsequent demonstration that brain lev- els of neurosteroids occur within a range known to be active at the GABAAR led to the proposal that they may act as endogenous regulators of GABAAR function (reviewed in Lambert et al., 1995). GABAA receptors are responsible for mediating the major- ity of fast inhibitory neurotransmission within the CNS and are the target of a number of clinically signiﬁcant compounds, including benzodiazepines (BDZ) such as diazepam and a variety of structurally diverse general anesthetics and anticonvulsants, including propofol, etomidate, and members of the barbiturate class, e.g., thiopentone (Olsen and Sieghart, 2009). This recep- tor class possesses a pentameric structure, surrounding a central anion conducting pore. To date, 19 subunits have been identiﬁed (α1–6, β1–3, γ1–3, δ, ε, θ, π, ρ1–3), that are divided into subfam- ilies based upon their amino acid homology (Olsen and Sieghart, 2008, 2009). These subunits exhibit distinct expression proﬁles and allow for the expression of ∼20–30 different GABAAR iso- forms within the mammalian CNS (Fritschy and Brunig, 2003; Olsen and Sieghart, 2008). The subunit composition regulates the pharmacological and biophysical properties of the GABAAR (Olsen and Sieghart, 2009), in addition to inﬂuencing the regional expression and cellular location (e.g., synaptic or extrasynaptic). GABAAR isoforms incorporating the γ2 subunit, in combination with α and β subunits are ubiquitously expressed throughout the brain (Wisden et al., 1992; Fritschy and Brunig, 2003) and are pre- dominantly, but not exclusively, located within the synapse, where they are responsible for mediating “phasic” GABAergic inhibition (Farrant and Nusser, 2005). In contrast, δ-containing GABAARs (δ-GABAARs) display a more discrete expression proﬁle, being primarily prevalent in the cerebellum, dentate gyrus, thalamus, striatum, and cortex (Wisden et al., 1992; Fritschy and Mohler, 1995) where they are expressed only at peri- and extrasynaptic locations (Nusser et al., 1998; Wei et al., 2003) and mediate a “tonic” form of GABAergic inhibition (Farrant and Nusser, 2005). The apparent sensitivity of native GABAARs to neurosteroid modulation is inﬂuenced by a variety of factors including the sub- unit composition of the receptor, phosphorylation reactions, and local metabolism (Belelli and Lambert, 2005). As an example of the ﬁrst, evidence from recombinant expression systems indicates www.frontiersin.org December 2011 | Volume 5 | Article 131 | 1