| First Author | Truitt JM | Year | 2016 |
| Journal | eNeuro | Volume | 3 |
| Issue | 5 | PubMed ID | 27822501 |
| Mgi Jnum | J:255941 | Mgi Id | MGI:6114473 |
| Doi | 10.1523/ENEURO.0256-16.2016 | Citation | Truitt JM, et al. (2016) Inhibition of IKKbeta Reduces Ethanol Consumption in C57BL/6J Mice. eNeuro 3(5):ENEURO.0256-16.2016 |
| abstractText | 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-kappaB (NF-kappaB) family of DNA transcription factors plays important roles in inflammatory diseases. The kinase IKKbeta mediates the phosphorylation and subsequent proteasomal degradation of cytosolic protein inhibitors of NF-kappaB, leading to activation of NF-kappaB. The role of IKKbeta 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 IKKbeta would limit/decrease drinking by preventing the activation of NF-kappaB. We studied the systemic effects of two pharmacological inhibitors of IKKbeta, 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 IKKbeta in mice genetically engineered with a conditional Ikkb deletion (Ikkb(F/F) ). Although IKKbeta was inhibited to some extent in astrocytes and microglia, neurons were a primary cellular target. Deletion of IKKbeta 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 IKKbeta decreased voluntary ethanol consumption, providing initial support for IKKbeta as a potential therapeutic target for alcohol abuse. |
