In conclusion, we have found that chronic alcohol consumption downregulates NF-κB and p50 homodimer in the PFC of human brain. These adaptations may be induced through several mechanisms that a) regulate transcription of the RELA gene, b) maintain the stoichiometry of p65 and p50 proteins, and c) control DNA-binding of p50 homodimer possibly via its phosphorylation (Figure 6). NF-κB may be targeted through the glutamate receptors, calcium influx and oxidative processes [15], [16], [25]–[28], all affected by cycles of alcohol consumption and withdrawal. Allostasis in the NF-κB system found in the present study may ensure tolerance and/or compensatory response to excessive stimulation in chronic alcoholics. Downregulation of the inhibitory p50 homodimer apparently contributes to the enhanced expression of genes regulated through κB elements in the PFC in alcoholics. Adaptations in the NF-κB system may be essential for persistent neuroplastic changes and neurodegeneration underlying dependence to alcohol and associated impairment of cognitive functions. An important role of the NF-κB system in alcoholism is emphasized by the recent animal transcriptome meta-analysis [78] and the human genetics findings. The NF-κB signaling pathway was
