TY - JOUR T1 - Inhibition of IKKβ Reduces Ethanol Consumption in C57BL/6J Mice JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0256-16.2016 VL - 3 IS - 5 SP - ENEURO.0256-16.2016 AU - Jay M. Truitt AU - Yuri A. Blednov AU - Jillian M. Benavidez AU - Mendy Black AU - Olga Ponomareva AU - Jade Law AU - Morgan Merriman AU - Sami Horani AU - Kelly Jameson AU - Amy W. Lasek AU - R. Adron Harris AU - R. Dayne Mayfield Y1 - 2016/09/01 UR - http://www.eneuro.org/content/3/5/ENEURO.0256-16.2016.abstract N2 - Proinflammatory pathways in neuronal and non-neuronal cells are implicated in the acute and chronic effects of alcohol exposure in animal models and humans. The nuclear factor-κB (NF-κB) family of DNA transcription factors plays important roles in inflammatory diseases. The kinase IKKβ mediates the phosphorylation and subsequent proteasomal degradation of cytosolic protein inhibitors of NF-κB, leading to activation of NF-κB. The role of IKKβ as a potential regulator of excessive alcohol drinking had not previously been investigated. Based on previous findings that the overactivation of innate immune/inflammatory signaling promotes ethanol consumption, we hypothesized that inhibiting IKKβ would limit/decrease drinking by preventing the 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 knock down IKKβ in mice genetically engineered with a conditional Ikkb deletion (IkkbF/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 the 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. ER -