The transcription factor CREB is a key downstream target of a variety of kinases, including cAMP–protein kinase A (PKA), Ca2+/calmodulin-dependent kinase, and extracellular-regulated kinase/mitogen-associated protein kinase (ERK/MAPK) (59, 60). The resulting activation/phosphorylation of CREB and recruitment of CREB-binding protein (CBP) along with other transcriptional components enables transcription of specific CREB target genes, including those implicated in long-term memory and plasticity as well as in the development of anxiety-like and alcohol-drinking behaviors, such as the neuropeptide Y (NPY) and the brain-derived neurotrophic factor (BDNF) (61–64). There is mounting evidence to support a role for phosphorylated CREB (pCREB) through a PKA-dependent mechanism and downstream CREB target genes, in the adaptive changes and behavioral effects associated with acute and chronic alcohol exposure [for review, see Ref. (65–68)]. Acute and chronic ethanol exposures have long been known to modulate the various steps of the cAMP-dependent pathways in the rodent brain and in other cell systems (69–71). Exposure to ethanol affects a cascade of events allowing for sustained translocation of PKA catalytic subunit into the nucleus (72), ultimately resulting in long-lasting increased CREB activation/phosphorylation (73)
