Gunn et al. GABAA receptors, neurosteroids, and stress forebrain structures that are important for the processing of stres- sor information. Moreover, the notion of a physiological role for CRH-induced neurosteroidogenesis is further supported by the observation that downstream G-protein coupled signaling path- ways (e.g., MAPK) associated with activation of CRH systems have already been implicated in neurosteroidogenesis (Tokuda et al., 2011; Figure 1). Interestingly, the dendritic release of various neuropeptides within the hypothalamus has been proposed as an important mechanism in the functional reorganization of neuronal networks (Ludwig and Leng, 2006) and may be involved in the coupling of the hypothalamic neurohypophysial system and the HPA axis dur- ing periods of stress (Engelmann et al., 2004). It is conceivable that other neuropeptides such as oxytocin, AVP, and neuropeptide Y (NPY), are similarly capable of stimulating or, indeed, inhibiting neurosteroid synthesis. How these neuromodulators may inﬂu- ence the coupling of neuronal networks thus warrants further investigation. Neuropeptides may not only inﬂuence the de novo synthesis of 3α-reduced steroids, but can additionally dynamically modulate the neurosteroid sensitivity of GABAARs by changing the phos- phorylation state of the receptor, or associated proteins. For exam- ple, in magnocellular neurons of the SON, synaptic GABAARs, while steroid-sensitive during pregnancy, become insensitive to 5α3α-THPROG 24 h after parturition (Brussaard et al., 1997). This dynamic shift in the pharmacology of the receptor, appeared to be caused by an oxytocin-induced change in the relative activity of endogenous phosphatases and PKC, acting to blunt the sensitivity of GABAARs to the progesterone metabolite (Koksma et al., 2003). Given that neuropeptide receptors share similar G-protein coupled signaling pathways, CRH, NPY, and AVP also have the potential to modulate GABAAR neurosteroid sensitivity. The physiological sig- niﬁcance of such a scenario has not been explored, although such studies will be complex as the impact of phosphorylation upon neurosteroid sensitivity of GABAARs is both kinase and neuron- speciﬁc (Fancsik et al., 2000; Brussaard and Koksma, 2003; Harney et al., 2003). NEUROPEPTIDES, NEUROSTEROIDS, AND REWARD PATHWAYS There may be a reciprocal relationship between processing stress and reward information within the brain, as several common brain structures are critically involved in their regulation. Thus, for example, the extended amygdala [comprising the BST, the CeA, and the posterior nucleus accumbens (NAc) shell], may mediate many of the motivational effects of opposing processes (i.e., the hedonic positive and negative emotional states that occur at dif- ferent stages of drug taking), associated with drug dependence (Koob and Le Moal, 2001). Interestingly, as noted above, the BST inﬂuences HPA activity via projections to the PVN and appears to be an important structure involved in the integration of stress- related information originating in limbic and forebrain inputs (Ulrich-Lai and Herman, 2009). In animal models, acute admin- istration of drugs of abuse causes activation of the HPA axis, an effect believed to facilitate drug reward by enhancing the activity of brain motivational circuits, resulting in the acquisition of drug- seeking behavior (reviewed in Koob, 2008). In contrast, the HPA response to drugs of abuse becomes blunted following repeated administration (Rasmussen et al., 2000; Semba et al., 2004), as high levels of glucocorticoids may feedback to negatively regulate the HPA axis (de Kloet et al., 2005; Koob, 2008). Additionally, elevated glucocorticoid levels associated with repeated HPA axis activation can “sensitize” extra-hypothalamic CRH systems (e.g., CeA) and norepinephrine (NE) systems in the BLA, known to be involved in behavioral responses to stressor exposure (Swanson and Sim- mons, 1989; Imaki et al., 1991; Makino et al., 1994). As activation of these extra-hypothalamic stress–sensitive targets characterizes the withdrawal/negative affect stage of addiction, their dysregu- lation may underpin at least some of the behavioral responses associated with chronic drug treatment and withdrawal (Koob and Kreek, 2007; Koob and Zorrilla, 2010). In agreement, sub- stantial evidence indicates that extra-hypothalamic CRH systems are activated during the development of dependence from ethanol and other drugs of abuse (Koob, 2008). Furthermore, a number of other anxiogenic (e.g., NE, dynorphin, orexin, AVP) and anx- iolytic (NPY) neuropeptides have similarly been associated with the transition to, and maintenance of, drug dependence (reviewed in Koob, 2008). As CRH administration induces an increase in the brain lev- els of 5α3α-THPROG, endogenous neurosteroids may not only be involved in regulating the activity of the HPA axis, but, given the close association of the stress and reward systems, they may additionally act as important modulators of the reward circuitry. Indirect support for a close association between stress and reward systems, comes from the clinical studies of drug addiction and major depression. Thus, Enoch et al. (2010) have recently reported an increased propensity particularly to cocaine addiction to seg- regate with speciﬁc polymorphisms of the GABAAR α2 subunit only when associated with a previous history of early life stress. Further, deep brain stimulation of the NAc signiﬁcantly improved clinical ratings of anhedonia, an inability to gain pleasure from previously pleasurable activities, in patients suffering from forms of depression resistant to pharmacological treatment (Schlaepfer et al., 2008) thus, suggesting a dysfunction of the reward circuitry. Interestingly, 5α-reductase is present in the NAc and the expression of this enzyme is known to be sensitive to acute stress (i.e., swim stress) in the mPFC (Sánchez et al., 2008) and to early chronic psychosocial stress in both the mPFC and NAc (Bortolato et al., 2011), suggesting that it may play a physiological role in both brain regions (Bortolato et al., 2011). In support, 5α3α-THPROG inﬂu- ences dopamine efﬂux in the NAc (Motzo et al., 1996; Rouge-Pont et al., 2002). Furthermore, the systemic administration and intra- accumbal infusion of 5α3α-THPROG in OVX rats signiﬁcantly reduced the immobility time in the forced swim test, an animal model of depression (Molina-Hernandez et al., 2005). Collectively, these ﬁndings are consistent with the proposal that the NAc may be an important site in mediating the putative antidepressant actions of neurosteroids. Moreover, the stress– protective actions of neurosteroids may contribute to such an effect as the NAc innervates several important stress-related brain structures including the BST, mPFC, BLA, in addition to several hypothalamic nuclei (Ulrich-Lai and Herman, 2009). A signiﬁcant body of work has investigated a possible relation- ship between neurosteroids acting at the GABAAR and ethanol. Frontiers in Neuroscience | Neuroendocrine Science December 2011 | Volume 5 | Article 131 | 12