8/11 Targeting Anti-inflammatory Gene Expression in Binge-like Drinking

Project Summary High Drinking in the Dark (HDID) mice have been selectively bred to drink to intoxication. HDID mice are genetically distinct and represent a unique genotype for drug screening. Many of the compounds that reduce drinking in other strains (e.g., C57BL/6J) do not reduce drinking in HDID mice, and also fail to reduce drinking in humans. Many INIA-Neuroimmune studies have found that alcohol alters inflammatory signaling. We employed a rigorous approach for testing whether several compounds targeting immune signaling could reduce binge-like drinking in HDID mice. To date, 14 out of 28 compounds tested in HDID mice were able to reduce binge-like drinking in HDID mice. Apremilast, a phosphodiesterase type 4 inhibitor and our most promising clinical target, and other compounds that reduced binge-like drinking have one thing in common - they increase anti-inflammatory (e.g. IL-10) signaling. These results offer a broadly unifying hypothesis for more mechanistic experiments to investigate how the balance of pro- and anti-inflammatory signaling regulates binge-like drinking in HDID mice. Here, we study this mechanism in the context of initiation of binge-like drinking, and determine whether this framework holds true under chronic binge drinking conditions. An overarching goal of this proposal is to identify and target anti-inflammatory signatures to reduce drinking and restore alcohol-induced changes in anti- and pro-inflammatory signaling in the brain. Specfic Aim 1 tests whether specific inflammatory signaling pathways contribute to binge-like drinking in iHDID mice using a combination of complementary molecular, genetic, pharmacological, and behavioral approaches in collaboration with INIA-N PIs Roberto, Mangieri, Bilbo, and Lasek. Specific Aim 2 tests whether chronic binge- like drinking is accompanied and/or regulated by anti-inflammatory gene expression in iHDID-1 mice. Aim 2 will employ informatics approaches to identify compounds for behavioral and molecular studies in collaboration with INIA-N PI Mayfield. This project also collaborates with INIA-Stress PIs Vazey/Mooreman and Becker/Lopez to test the effects of promising compounds on other behaviors, and shares the HDID and HS/Npt mouse lines as unique resources developed and maintained under this award with investigators nationwide.