title: Transcriptional control of maladaptive and protective responses in alcoholics: a role of the NF-κB system.
abstract: Alcohol dependence and associated cognitive impairment appear to result from maladaptive neuroplasticity in response to chronic alcohol consumption, neuroinflammation and neurodegeneration. The inherent stability of behavioral alterations associated with the addicted state suggests that transcriptional and epigenetic mechanisms are operative. NF-κB transcription factors are regulators of synaptic plasticity and inflammation, and responsive to a variety of stimuli including alcohol. These factors are abundant in the brain where they have diverse functions that depend on the composition of the NF-κB complex and cellular context. In neuron cell bodies, NF-κB is constitutively active, and involved in neuronal injury and neuroprotection. However, at the synapse, NF-κB is present in a latent form and upon activation is transported to the cell nucleus. In glia, NF-κB is inducible and regulates inflammatory processes that exacerbate alcohol-induced neurodegeneration. Animal studies demonstrate that acute alcohol exposure transiently activates NF-κB, which induces neuroinflammatory responses and neurodegeneration. Postmortem studies of brains of human alcoholics suggest that repeated cycles of alcohol consumption and withdrawal cause adaptive changes in the NF-κB system that may permit the system to better tolerate excessive stimulation. This type of tolerance, ensuring a low degree of responsiveness to applied stimuli, apparently differs from that in the immune system, and may represent a compensatory response that protects brain cells against alcohol neurotoxicity. This view is supported by findings showing preferential downregulation of pro-apoptotic gene expression in the affected brain areas in human alcoholics. Although further verification is needed, we speculate that NF-κB-driven neuroinflammation and disruption to neuroplasticity play a significant role in regulating alcohol dependence and cognitive impairment.
authors.affiliation: Division of Biological Research on Drug Dependence, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Yakovleva
authors.forename: Igor
authors.initials: I
authors.lastname: Bazov
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
authors.forename: Georgy
authors.initials: G
authors.lastname: Bakalkin
mesh_terms: D000437:Alcoholism / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D016328:NF-kappa B