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.
The authors declare no competing financial interests.
Research was supported by NIH/NIAAA grants AA012404, AA013520, AA012404, and AA0209260.