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
VO 3
IS 5
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/3/5/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. 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.