Inhibition of IKKβ 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-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 expressingCrerecombinase was injected into the nucleus accumbens and central amygdala to selectively knock down IKKβ in mice genetically engineered with a conditionalIkkbdeletion (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.
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin , Austin, Texas 78712.
Jay M
JM
Truitt
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin , Austin, Texas 78712.
Yuri A
YA
Blednov
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin , Austin, Texas 78712.
Jillian M
JM
Benavidez
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin , Austin, Texas 78712.
Mendy
M
Black
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin , Austin, Texas 78712.
Olga
O
Ponomareva
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin , Austin, Texas 78712.
Jade
J
Law
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin , Austin, Texas 78712.
Morgan
0000-0002-6459-3541
M
Merriman
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin , Austin, Texas 78712.
Sami
0000-0002-2601-6372
S
Horani
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin , Austin, Texas 78712.
Kelly
K
Jameson
Department of Psychiatry, University of Illinois at Chicago , Chicago, Illinois 60612.
Amy W
AW
Lasek
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin , Austin, Texas 78712.
R Adron
RA
Harris
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin , Austin, Texas 78712.
R Dayne
0000-0002-8045-1789
RD
Mayfield
D000427:Alcohol Deterrents / Q000494:pharmacology; D000428:Alcohol Drinking / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage; D005518:Food Preferences / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012439:Saccharin
D000427:Alcohol Deterrents; D002492:Central Nervous System Depressants; D016328:NF-kappa B; D012333:RNA, Messenger; D000431:Ethanol; D051550:I-kappa B Kinase; D012439:Saccharin
Cre recombinase; DID; TPCA-1; alcohol; astrocytes; binge drinking; central amygdala; microglia; neurons; nucleus accumbens; sulfasalazine