RT Journal Article SR Electronic T1 Inhibition of IKKβ Reduces Ethanol Consumption in C57BL/6J Mice JF eneuro JO eneuro FD Society for Neuroscience SP ENEURO.0256-16.2016 DO 10.1523/ENEURO.0256-16.2016 A1 Jay M. Truitt A1 Yuri A. Blednov A1 Jillian M. Benavidez A1 Mendy Black A1 Olga Ponomareva A1 Jade Law A1 Morgan Merriman A1 Sami Horani A1 Kelly Jameson A1 Amy W. Lasek A1 R. Adron Harris A1 R. Dayne Mayfield YR 2016 UL http://www.eneuro.org/content/early/2016/10/19/ENEURO.0256-16.2016.abstract AB Proinflammatory pathways in neuronal and non-neuronal cells are implicated in the acute and chronic effects of alcohol exposure in animal models and humans. Nuclear factor kappa-B (NF-κB) is a transcription factor for proinflammatory chemokines and cytokines. Inhibitory kappa-B kinase beta (IKKβ) regulates the NF-κB cascade by targeting the inhibitor of NF-κB (IκB) for degradation and represents a point of convergence for many extracellular signals. However, the role of IKKβ had not been investigated as a potential regulator of excessive alcohol drinking. Based on previous findings that overactivation of innate immune/inflammatory signaling promotes ethanol consumption, we hypothesized that inhibiting IKKβ would limit/decrease drinking by preventing activation of NF-κB. We studied the systemic effects of two pharmacological inhibitors of IKKβ, TPCA-1 and sulfasalazine, on ethanol intake using continuous and limited access two-bottle choice drinking tests in C57BL/6J mice. In both tests, TPCA-1 and sulfasalazine reduced ethanol intake and preference without changing total fluid intake or sweet taste preference. A virus expressing Cre recombinase was injected into the nucleus accumbens and central amygdala to selectively knockdown IKKβ in mice genetically engineered with a conditional Ikkβ deletion (IkkβF/F). Although IKKβ was inhibited to some extent in astrocytes and microglia, neurons were a primary cellular target. Deletion of IKKβ in either brain region reduced ethanol intake and preference in the continuous access two-bottle choice test without altering preference for sucrose. Pharmacological and genetic inhibition of IKKβ decreased voluntary ethanol consumption, providing initial support for IKKβ as a potential therapeutic target for alcohol abuse.Significance Statement: Alcoholism is a devastating disease with few pharmacological treatment options. The disease pathophysiology is unknown, but it is increasingly evident that proinflammatory signaling plays a role. NF-κB is a transcription factor that controls the expression of genes that are involved in inflammation and immunity. IKKβ mediates numerous inflammatory pathways and is responsible for disinhibiting NF-κB. The role of IKKβ in alcohol drinking had not previously been investigated. Our goal was to assess the peripheral and central effects of IKKβ on chronic and binge-like alcohol consumption and its potential role as a therapeutic target to reduce drinking.