Though early findings showed that CRFBP inhibits CRF/CRF1R signaling (Potter et al., 1991), more recent data suggest that interactions with CRFBP may be required for some actions of CRF at the CRF2R (Ungless et al., 2003; Wang et al., 2007). CRF2Rs have a more restricted distribution than the CRF1 subtype and are primarily localized to structures involved in behavioral stress responses, including: the dorsal raphe (DR) nucleus, lateral septum (LS), bed nucleus of the stria terminalis BNST, AMG, and HYP, (Cavalcante et al., 2006; Chalmers et al., 1995; Chen et al., 2011; Kuperman et al., 2010; Li et al., 2002; Van Pett et al., 2000). Some CRF2 receptor-expressing regions receive innervation from multiple

sites containing different CRF/Ucn ligands, and studies using pharmacological tools may therefore be insufficient to Tanespimycin cell line identify the functional role of the respective endogenous input. Effects of Ucn:s on stress responses are more restricted but also more complex than those of CRF. In contrast to CRF, Ucn:s do not play a direct role in HPA axis responses (Kageyama et al., 2003; Nemoto et al., 2009). Ucn/CRF2R activation has repeatedly been shown to result in reduction of anxiety-like behavior (anxiolysis) and recovery from stress (Coste et al., 2000; Tanaka and Telegdy,

2008; Todorovic et al., 2007; Valdez et al., 2003), i.e., effects opposite those mediated by CRF through actions at CRF1Rs. However, Ibrutinib research buy CRF2R signaling can also drive stress-induced increases in anxiety (Henry et al., 2006), aversion (Land et al., 2008), and alcohol consumption (Pastor et al., 2011), while social defeat stress potently activates CRF2R-expressing neurons of the medial AMG (Fekete et al., 2009). Ucn:s also play a role in long-term stress adaptation (Neufeld-Cohen et al., 2010a, 2010b). It is clear from the complexity of functional consequences that Ucn/CRF2R signaling does not serve simply as an “antialarm” system opposing CRF actions. Converging lines of evidence indicate over that endogenous Ucn1 promotes alcohol consumption (Bachtell et al., 2003; Giardino et al.,

2011a; Ryabinin et al., 2012; Ryabinin and Weitemier, 2006). In rodents, Ucn1-containing neurons within the centrally projecting Edinger-Westphal nucleus (EWcp) are particularly sensitive to voluntary alcohol consumption (Anacker et al., 2011; Bachtell et al., 2003; Kaur and Ryabinin, 2010; Ryabinin et al., 2003; Weitemier et al., 2001). The neuropeptide-containing neurons of the EWcp send Ucn1-positive axons to brain regions that include the LS and DR, structures involved in behavioral stress responses (Bachtell et al., 2004; Bittencourt et al., 1999; Kozicz et al., 2011). Higher levels of EWcp-Ucn1 protein were associated with higher alcohol consumption and alcohol-induced reward in rodent strains that vary in alcohol-related behaviors (Bachtell et al., 2003; Fonareva et al., 2009; Kiianmaa et al.