PROJECT SUMMARY Methamphetamine (METH) use disorder is a rising public health crisis to which there are no available FDA- approved therapeutics. METH is a highly addictive and neurotoxic substance that can trigger neuroinflammation and induce long-lasting gene expression changes across the brain reward system. Indeed, epigenetic enzymes have shown the ability to regulate both drug-induced transcriptional changes and the expression of inflammatory cytokines. For instance, it has been shown that changes in histone acetylation can drive transcriptional and neuroinflammatory responses to METH exposure. Interestingly, expression of the histone acetylation reader, Brd4, and histone acetyltransferase, P300/CBP, increases following cocaine, alcohol and opioid exposure. Further, pharmacological inhibition of these enzymes has been shown to curb drug-seeking in humans and decrease neuroinflammation, altogether suggesting that Brd4 and P300/CBP may play important roles in addiction pathophysiology. However, the potential role of Brd4 and P300/CBP in METH reinforcement and related inflammatory signaling remains poorly understood. We therefore propose to study the role of Brd4 and P300/CBP in METH reinforcement and METH-induced neuroinflammation by using a mouse model of METH intravenous self-administration. We will inhibit Brd4 and P300/CBP with a novel small molecule inhibitor (EP32010) that is brain-penetrant and highly selective for Brd4 and P300/CBP. We will test whether dual inhibition of Brd4 and P300/CBP can curb METH-taking, relapse, as well as dampen neuroinflammatory responses to the drug. Taken together, these studies will sharpen our understanding of the epigenetic mechanisms underlying the reinforcing and neuroinflammatory properties of METH, and how these processes can help shape the course of METH use disorder. More broadly, we hope results from these studies will pave new avenues toward the development of effective cessation therapeutics.