Role of the IKKβ/NF-κB pathway in alcoholism

Pro-inflammatory neuroimmune signaling pathways are implicated in the acute and chronic effects of alcohol exposure. Genetic association studies in humans, gene expression microarray studies in postmortem brains of alcoholics, transcriptome meta-analysis in rodents, and drinking models in mice support the role of neuroimmune signaling in alcohol abuse disorder. Nuclear factor kappa-B (NF-κB) is a ubiquitously expressed transcription factor that controls the expression of genes important for innate- and adaptive-immune responses, cell proliferation/death, and inflammation. More specifically, the NF-κB canonical pathway is responsible for the expression of pro-inflammatory genes. The inhibitory kappa-B kinase (IKK) complex, composed of IKKα, IKKβ, and IKKγ represents a point of convergence for many extracellular signals and regulates the NF-κB canonical pathway by targeting the inhibitor of NF-κB (IκB) for degradation. NF-κB is disinhibited, translocates to the nucleus, and acts as a transcription factor for numerous pro-inflammatory chemokines and cytokines. However, IKKβ is the only member of the IKK complex that specifically mediates this pathway. As such, I hypothesized that inhibiting IKKβ/NF-κB pathway would limit/decrease voluntary ethanol consumption. This was studied by determining the brain region and cell type-specificity of all the IKK isoforms. It was observed that all IKKs were primarily expressed in neurons and ubiquitously expressed throughout the brain regions studied [prefrontal cortex (PFC), nucleus accumbens (NAc), amygdala (AMY), and ventral tegmental area (VTA)]. Subsequently, the effects of inhibiting/knocking down IKKβ were investigated both systemically and centrally to determine the effects on voluntary ethanol drinking. It was observed that both antagonizing IKKβ peripherally and genetically knocking it down centrally in the NAc and central amygdala (CeA) reduced voluntary ethanol consumption and preference in two bottle choice (2BC) ethanol drinking paradigms. Lastly, ethanol-responsive microRNAs were explored in the PFC, NAc, and AMY. Several differentially expressed MicroRNAs were discovered that were either predicted/validated to target genes of the IKKβ/NF-κB pathway. One candidate, let-7g, was manipulated in vivo to determine its effect on voluntary ethanol drinking behaviors, however, no significant phenotypes were observed. These results demonstrate that blocking IKKβ decreases voluntary ethanol consumption and indicate its role as a potential therapeutic target for alcohol abuse.