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Inhibition of the Inflammasome Signaling Cascade Reduces Alcohol Consumption in Female But Not Male Mice
Author(s) -
Lowe Patrick P.,
Cho Yeonhee,
Tornai David,
Coban Sahin,
Catalano Donna,
Szabo Gyongyi
Publication year - 2020
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.14272
Subject(s) - inflammasome , alcohol , alcohol use disorder , receptor , neuroinflammation , addiction , alcohol consumption , antagonist , pharmacology , medicine , receptor antagonist , ethanol , inflammation , psychology , endocrinology , chemistry , psychiatry , biochemistry
Background Alcohol use disorder is a significant societal and medical burden that is associated with both organ pathology and addiction. Excessive alcohol use results in neuroinflammation characterized by activation of the inflammasome, a multiprotein complex, and IL‐1β increase in the brain. Recent studies suggest that inflammation could contribute to alcohol addiction. Here, we targeted components of the NOD‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome cascade, which senses and responds to immunologic stimuli, to determine whether NLRP3 inhibition modulates alcohol consumption. Methods C57BL/6J male and female mice were provided a 2‐bottle choice of alcohol at increasing concentrations (3, 6, 9, and 12%, 4 days each) or water, and some were treated with daily injections of an NLRP3 inhibitor (MCC950), a caspase‐1 inhibitor (VX765), IL‐1 receptor antagonist (IL‐1ra; anakinra), or vehicle injection. Results Treatment with VX765, MCC950, and IL‐1ra significantly reduced alcohol consumption and preference in female mice ( p < 0.05). Treatment with MCC950 and IL‐1ra reduced alcohol consumption, while IL‐1ra reduced alcohol preference in male mice ( p < 0.05). VX765 did not affect alcohol consumption or preference in male mice. Conclusions These findings highlight gender differences in alcohol preference and demonstrate that inhibition of different steps in inflammasome signaling can reduce alcohol consumption in females. Inhibition of NLRP3 inflammasome activation and the inflammasome‐IL‐1β cascade opens novel insights into the development of new therapies to address alcohol use disorder in an era of targeted and precision medicine.