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) and downstream expression of many target genes (74). In this context, abnormal PKA-dependent CREB functioning has been implicated in the molecular mechanisms of neuroplasticity that underlie alcoholism and alcohol drinking. There is evidence for a biphasic temporal effect of ethanol on cAMP–PKA-dependent signaling cascade with acute and prolonged exposure to ethanol potentiating (75) and decreasing (76, 77), respectively, adenylyl cyclase–cAMP–PKA activity in the cortex and HPC (78) in mice. Using a combination of genetic or pharmacological approaches, Drosophila and rodents studies have shown that maintaining integrity of the cAMP–PKA activity is central to establishing sensitivity to the sedative effect of ethanol as well as in modulating ethanol consumption (79–81). Acute withdrawal (24 h) from chronic ethanol treatment produced a decrease in Ser133–pCREB within specific neurocircuitry of the frontal, parietal, and piriform cortex in rats (82), suggesting the possibility that CREB-dependent events in these cortical structures may be involved in the development of alcohol dependence. Among the mechanisms responsible for reduced
