Inhibition of IKK beta Reduces Ethanol Consumption in C57BL/6J Mice

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-kappa B (NF-kappa B) family of DNA transcription factors plays important roles in inflammatory diseases. The kinase IKK beta mediates the phosphorylation and subsequent proteasomal degradation of cytosolic protein inhibitors of NF-kappa B, leading to activation of NF-kappa B. The role of IKK beta 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 IKK beta would limit/decrease drinking by preventing the activation of NF-kappa B. We studied the systemic effects of two pharmacological inhibitors of IKK beta, 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 IKK beta in mice genetically engineered with a conditional Ikkb deletion (IkkbF/F). Although IKK beta was inhibited to some extent in astrocytes and microglia, neurons were a primary cellular target. Deletion of IKK beta 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 IKK beta decreased voluntary ethanol consumption, providing initial support for IKK beta as a potential therapeutic target for alcohol abuse.