# Domain- and protein-selective BET mechanisms in cocaine-seeking behaviors > **NIH NIH R01** · UNIVERSITY OF CONNECTICUT STORRS · 2024 · $525,380 ## Abstract Project Summary Epigenetic pharmacotherapy for substance use disorder (SUD) is a rapidly expanding area of research. With the ability to bind to acetylated histones and regulate drug-induced transcriptional adaptations, members of the bromodomain and extra-terminal domain (BET) family of proteins (BRD2, BRD3, BRD4 and BRDT) have emerged as promising therapeutic targets. To date, however, only pan-BET bromodomain inhibitors, small molecules that bind to both bromodomains (BD1 and BD2) within all BET proteins, have been tested in SUD- related experiments. The use of these non-selective pharmacological inhibitors in SUD models limits our mechanistic understanding of individual BET proteins, bromodomain-selective functions (BD1 vs. BD2), and non- bromodomain BET interactions that regulate drug-induced neurobehavioral adaptations. New evidence from our laboratory indicates that selectively targeting individual BET domains and proteins is a novel and effective strategy to reduce cocaine-induced behavioral and transcriptional responses without causing sides effects observed with pan-BET inhibitors. To build on these exciting data and to advance the field of epigenetic pharmacotherapy for SUD, we propose to use highly selective, clinically relevant treatments, viral-mediated approaches, and multiomic analysis to investigate domain- and protein-specific mechanisms of BET proteins during cocaine-seeking behaviors. To achieve these goals, we will first investigate the behavioral and cell type- specific transcriptomic responses of domain-selective BET inhibitors in cocaine economic demand and reinstatement procedures. Next, using co-immunoprecipitation and mass-spectrometry, we will characterize BRD4 interactome changes following short- and intermittent-access cocaine self-administration, and in functional studies, we will use newly developed tools to identify a role for non-bromodomain mechanisms of BRD4 in cocaine self-administration. Finally, we will interrogate novel transcriptional and behavioral roles for BRD2 in cocaine-seeking behaviors. Together, these experiments will provide significant contributions to the field of addiction epigenetics as well as novel therapeutic targets to reduce cocaine use and relapse. ## Key facts - **NIH application ID:** 10896204 - **Project number:** 5R01DA058700-02 - **Recipient organization:** UNIVERSITY OF CONNECTICUT STORRS - **Principal Investigator:** Gregory Charles Sartor - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $525,380 - **Award type:** 5 - **Project period:** 2023-08-01 → 2028-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10896204 ## Citation > US National Institutes of Health, RePORTER application 10896204, Domain- and protein-selective BET mechanisms in cocaine-seeking behaviors (5R01DA058700-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10896204. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*