, 2011). Since induction of Ras in NAc by chronic cocaine and chronic stress would be expected to activate CREB, and CREB in this region has previously been shown to oppose cocaine reward and promote depression-like BIBW2992 purchase behavior (Barrot et al., 2002, Blendy, 2006, Carlezon et al., 2005 and Pliakas et al., 2001), we focused on this protein further. We show that G9a overexpression in NAc, which represses Ras expression, also reduces levels of phospho-CREB in this brain

region. Moreover, we show that local knockdown of endogenous CREB in NAc exerts antidepressant actions in the social defeat and other behavioral assays, consistent with several prior studies of CREB action in addiction and depression models. We have also shown that genome-wide patterns of phospho-CREB binding to gene promoters in NAc of susceptible mice after chronic social defeat stress are reversed by chronic R428 molecular weight antidepressant treatment and not seen in unsusceptible animals (Wilkinson et al., 2009).

Furthermore, microarray analyses of NAc obtained from CREB-overexpressing mice revealed that CREB activity in NAc was sufficient to induce H-Ras1 expression in this brain region ( McClung and Nestler, 2003), similar to that observed here with both chronic cocaine and chronic stress. Likewise, overexpression of mCREB, a dominant-negative form of CREB, reduced H-Ras1 expression in NAc ( McClung and Nestler, 2003) and induced antidepressant-like effects in simple behavioral tests ( Barrot et al., 2002, Carlezon et al., 2005 and Pliakas et al., 2001). These data indicate a role for CREB activity in the potentiation of Ras expression, in which Ras may act, through a positive feedback loop, to increase its own expression by enhancing downstream CREB phosphorylation and activity ( Figure 8). Taken together, BDNF-TrkB-Ras-CREB signaling in NAc may be one pathway through which both drugs of abuse and stress trigger shared molecular, cellular, and behavioral adaptations ADP ribosylation factor ( Nestler et al., 2002, Pierce and Bari, 2001 and Thomas et al., 2008). The contribution of the core and shell subdivisions of NAc to the phenomena examined here remains

unknown. While the core and shell subserve distinct functions in drug and stress models (e.g., Di Ciano et al., 2008), the viral manipulations used in the current study cannot reliably distinguish these subregions, leaving the examination of this important question to future investigations. Depressive illnesses are among the most prevalent psychiatric disorders in the United States, afflicting ∼18% of the total population (Kessler et al., 2003). Only ∼40% of all individuals treated with available antidepressants experience a full remission of symptoms, underscoring the high demand for better treatments (Berton and Nestler, 2006 and Covington et al., 2010). Developing newer treatments has been limited by a scarcity of knowledge concerning the molecular biology of depression (Krishnan and Nestler, 2008).