Withdrawal from alcohol results in neuronal excitation [1], [65], [66] through activation of glutamate receptors and calcium influx; both stimuli activate NF-κB [15], [16], [25]–[27]. Cycles of alcohol intoxication and withdrawal, which initially activate NF-κB, when repeated over years may lead to adaptations in NF-κB that tolerate excessive stimulation. This hypothesis is supported by animal studies demonstrating that acute ethanol administration activates the NF-κB system in the brain [67], [68], which is then downregulated when ethanol is administered for the next three weeks [67]. Another adaptation to chronic alcohol consumption is the downregulation of the p50 homodimer, a dominant κB-binding factor in human cortex. This apparently results in derepression of genes regulated through κB-elements in their promoters. These types of adaptations, ensuring a low responsiveness and/or compensatory response to chronic stimulation, differ from that observed in the immune system [69], [70], which is based on the over-expression of the inhibitory p50 subunit.
