CREB signaling is increased in the DRN, with the expression of 67 downstream targets altered (Supplementary Table 4). CREB must be phosphorylated to be active and acute alcohol increases phosphorylated CREB (p-CREB) in the CeA and medial amygdala in P but not NP rats (Pandey et al., 2005). Increasing p-CREB in the CeA of P rats, by activating protein kinase A, decreases anxiety and ethanol consumption (Pandey et al., 2005). CREB signaling activates genes necessary for the survival of neurons under stress (Volakakis et al., 2010). CREB can be activated by multiple kinases, several of which are themselves altered, e.g. Camk4 (3.0-fold), Camk2b (1.3-fold), and Protein Kinase A (Prkaca −1.3-fold). Genes induced by CREB include NR4A nuclear receptors (Nr4a1, Nr4a2 and Nr4a3), with expression increased 3- to 6-fold in the binge-drinking adolescents. These receptors are necessary for the increased transcription of some of the neuroprotective genes downstream of CREB (Volakakis et al., 2010). Ppargc1a expression is also increased, and it is responsible for inducing another set of neuroprotective genes that respond to oxidative stress (Volakakis et al., 2010). The increased
