Gunn et al. GABAA receptors, neurosteroids, and stress Thus, in the ﬁnal section we will speciﬁcally focus on the putative while promoting ethanol consumption in non-dependent animals role of neurosteroids in the actions of alcohol. (Morrow et al., 2001). Moreover, tolerance to the ethanol-induced increase in neurosteroid levels developed in alcohol-dependent ETHANOL AND NEUROSTEROIDS animals (Khisti et al., 2005) and this adaptation may contribute to Neurosteroids have been proposed as important mediators of the excessive alcohol consumption in such animals (reviewed in ethanol sensitivity and dysregulation of ethanol-induced neu- Morrow et al., 2006). Conversely, heightened ethanol sensitivity, rosteroidogenesis has been associated with an increased risk of associated with increased neurosteroid levels has been suggested alcoholism (Morrow et al., 2006). Thus, a number of studies have to prevent excessive alcohol consumption (Morrow et al., 2006). indicated that increased neurosteroidogenesis within the brain Thus, restoration of ethanol sensitivity may have a therapeu- contributes to some of the behavioral and electrophysiological tic advantage for the treatment of alcohol dependence, but this actions associated with ethanol administration (VanDoren et al., remains to be tested in humans. 2000; Khisti et al., 2003; Sanna et al., 2004; Morrow et al., 2006; Interestingly, in addition to CRH, other anxiogenic neuropep- Izumi et al., 2007; Boyd et al., 2010; Figure 1). For example, acute tides have been consistently implicated in the development of ethanol treatment in CA1 pyramidal cells has been reported to alcohol dependence (Heilig and Koob, 2007). Thus, the poten- stimulate neurosteroid synthesis, resulting in an increase in the tial of these neuropeptide signaling systems to inﬂuence neu- peak amplitude and a prolongation of the decay time course rosteroidogenesis during the development of alcohol and indeed, of mIPSCs recorded from these neurons (Sanna et al., 2004). other types of drug dependence, deserves further investigation. An Moreover, acute ethanol (60 mM) completely blocked LTP in improved understanding of how neurosteroids and neuropeptide- rat hippocampal slices, an effect attenuated by inhibition of 5α- mediated signaling systems interact at different levels of the neu- reductase by ﬁnasteride, or by the neurosteroid sequestering agent, roaxis may provide insights into the pathology of not only alcohol γ-cyclodextrin (Izumi et al., 2007; Tokuda et al., 2011). These dependence, but also that of other drugs of abuse. observations implicate neurosteroidogenesis in the suppression of LTP by ethanol. Additionally, acute ethanol application increases SUMMARY AND CONCLUSION the frequency of mIPSCs recorded from CA1 pyramidal neurons. Since the seminal ﬁnding that mild stress elevates brain levels of However, in contrast to the ethanol effect upon mIPSC kinetics, neurosteroids in rodents (Purdy et al., 1991), a growing body of this action is not mimicked by a neurosteroid precursor (prog- evidence has implicated GABAAR-active neurosteroids as impor- esterone) or by CP34 a TSPO “agonist,” suggesting this apparent tant mediators of the complex neuronal adaptations underpinning presynaptic effect of ethanol to be independent of neurosteroid the response to acute and chronic stress challenges. Moreover, production (Sanna et al., 2004). A similar presynaptic effect of neurosteroids may represent important but overlooked molecular ethanol occurs in the cerebellum (Carta et al., 2004) and amyg- players of the early programming of the stress response. dala (Roberto et al., 2003; Nie et al., 2004). Interestingly, in the Converging data from the clinic and from animal models latter this effect appears to be mediated by the activation of CRH indicates a close association between early life stress experiences receptor 1 (CRH R1; Nie et al., 2004). and the development of highly debilitating psychiatric conditions A role for CRH in ethanol actions is consistent with evi- including anxiety disorders, depression, and drug addiction. Of dence from animal models demonstrating the activation of extra- relevance to neurosteroids, the impairment of brain signals medi- hypothalamic CRH systems in the development of alcohol depen- ated by GABAARs is associated with early life adversities. However, dence (Heilig and Koob, 2007; Koob, 2008), although whether the contribution made by these potent, endogenous, GABAAR the effects of ethanol in the hippocampus involve CRH is not modulators to the pathophysiology of these psychiatric conditions known. As noted above, CRH also increases neurosteroid levels, is only now beginning to emerge. This realization is being comple- although the speciﬁc mechanisms underpinning such an action mented by a better understanding of the role neurosteroids play are not fully elucidated (Torres et al., 2001). Interestingly, PKC, during early neuronal development and of their involvement in and in particular the PKCε isoform, appears to be an impor- the programming of the stress response. Collectively, this research tant mediator of CRH and ethanol-induced GABA release in suggests that neurosteroids, or drugs that inﬂuence neurosteroid the CeA (Bajo et al., 2008). Additionally, this enzyme inﬂuences synthesis, may offer a novel therapeutic approach to the treatment the sensitivity of GABAARs to neurosteroids (Hodge et al., 1999; of stress-related disturbances. Fancsik et al., 2000; Brussaard and Koksma, 2003; Harney et al., Many psychiatric disturbances have a recognized mixed genetic 2003). Thus, a PKC-induced reduction in the neurosteroid sensi- and environmental basis such that a genetic predisposition does tivity of GABAARs (Brussaard and Koksma, 2003; Harney et al., not always imply an abnormal phenotype in the absence of signiﬁ- 2003 but see Fancsik et al., 2000) following ethanol administra- cant environmental challenges, e.g., early life stress. As an example, tion has been suggested to contribute to an increase in alcohol polymorphisms of the GABAAR α2 subunit, a protein that is highly consumption as a consequence of the reduced neurosteroid sen- expressed in stress-related neuronal circuits, confer susceptibility sitivity (Morrow et al., 2006, also see below). However, the rela- to cocaine addiction, but only when these genetic abnormalities tionship between alcohol intake and neurosteroids is complex, are coincident with previous traumatic early life stress experiences being both context and dose-related. Thus, for example, low doses (Enoch et al., 2010). Although enzyme expression and function of 5α3α-THPROG increased while high doses reduced alcohol is known to be sensitive to epigenetic regulation, the molecu- intake in C57 mice (Ford et al., 2005). Equally, the progesterone lar mechanisms governing the neuron-selective expression and metabolite reduced alcohol intake in alcohol-dependent rodents, function of the neurosteroid enzymatic machinery are still poorly www.frontiersin.org December 2011 | Volume 5 | Article 131 | 13