Dataset Information

Cocaine-induced changes in the BRD4 interactome identifies casein kinase 1 epsilon as a therapeutic target

ABSTRACT: Recent research has revealed that BRD4, a bromodomain and extra terminal domain (BET) epigenetic ‘reader’ protein, plays an essential role in regulating behavioral and molecular responses to cocaine. To date, the roles of BRD4 and other BET proteins in substance use disorder (SUD) models have been mainly studied using small molecule inhibitors that block the bromodomain interactions with acetylated histones. In other disease models, non-bromodomain BRD4-protein interactions have also been shown to play an important role in BRD4’s molecular functions, but these interactions have yet to be studied in SUD models. Here, using BRD4 co-immunoprecipitation coupled to tandem mass spectrometry, we identified several putative BRD4-interacting proteins in the nucleus accumbens (NAc) that are altered by acute or repeated cocaine exposure in male and female Sprague Dawley rats. In BRD4-immunoprecipitated samples, gene ontology molecular function analysis revealed an enrichment of pathways associated with polymerase activity, SH3 domain binding, and chromatin-protein-adaptor activity in the cocaine treated groups. Notably, casein kinase 1 epsilon (CK1ε), a protein previously implicated in SUDs, was identified as a putative BRD4-interacting protein, and this association was increased following repeated cocaine injections. However, no significant change in total CK1ε protein expression was observed in the NAc via western blot following acute or repeated cocaine treatment. In additional experiments, we sought to determine the effects of CK1ε inhibition on the expression of a cocaine-related memory. Pharmacological inhibition of CK1ε with PF-4800567 diminished the expression of cocaine conditioned place preference. In a separate cohort of rats, an acute injection of PF-4800567 did not alter locomotor activity and anxiety-like behavior in the open field test. Collectively, these findings suggest that several novel proteins, including CK1ε, may play a role in BRD4-mediated molecular adaptations to cocaine exposure, and that CK1ε represents a potential target for future investigation in animal models of cocaine-seeking behavior.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain

DISEASE(S): Substance Abuse

SUBMITTER: Jeremy Balsbaugh

LAB HEAD: Jeremy L.

PROVIDER: PXD065009 | Pride | 2026-01-22

REPOSITORIES: Pride

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			Action	DRS
	20230928_jlb_CBabigian_Sartor_254_200ng_OTOThcdETDDecTree_60min_Wat25cmBEH_1.raw	Raw
	20230928_jlb_CBabigian_Sartor_255_200ng_OTOThcdETDDecTree_60min_Wat25cmBEH_1.raw	Raw
	20230928_jlb_CBabigian_Sartor_256_200ng_OTOThcdETDDecTree_60min_Wat25cmBEH_1.raw	Raw
	20230928_jlb_CBabigian_Sartor_257_200ng_OTOThcdETDDecTree_60min_Wat25cmBEH_1.raw	Raw
	20230928_jlb_CBabigian_Sartor_258_200ng_OTOThcdETDDecTree_60min_Wat25cmBEH_1.raw	Raw

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Cocaine-Induced Changes in the BRD4 Interactome Identifies Casein Kinase 1 Epsilon as a Therapeutic Target.

Seyednejad Afshin A Sacko Tyler J TJ Babigian Christopher J CJ Moore Timothy E TE Xiao Shiying S Liddle Jennifer C JC Sartor Gregory C GC

Journal of neurochemistry 20260101 1

Recent research has revealed that BRD4, a bromodomain and extra terminal domain (BET) epigenetic "reader" protein, plays an essential role in regulating behavioral and molecular responses to cocaine. To date, the roles of BRD4 and other BET proteins in substance use disorder (SUD) models have been mainly studied using small molecule inhibitors that block the bromodomain interactions with acetylated histones. In other disease models, non-bromodomain BRD4-protein interactions have also been shown ...[more]

PMID: 41521463

Similar Datasets

Project description:Bromodomain and extra terminal domain (BET) epigenetic ‘reader’ proteins are key regulators of both behavioral and molecular responses to cocaine. In substance use disorder (SUD) models, BET function has primarily been investigated using small molecule inhibitors that prevent both bromodomains of BET proteins from interacting with acetylated histones. Although these inhibitors have been shown to be effective in SUD models, the potential adverse effects of pan-BET inhibition may restrict translational applications. Recently, RVX-208 (also known as apabetalone), a clinically tested, domain-selective BET inhibitor, was found to reduce cocaine conditioned responses and cocaine-induced gene expression in the nucleus accumbens (NAc), while avoiding the learning and memory impairments associated with pan-BET inhibitors. However, the effectiveness of RVX-208 in cocaine self-administration procedures remains unclear. Here, we investigated whether repeated RVX-208 treatment during abstinence altered cocaine seeking-behavior in rats trained to self-administer cocaine. Male and female Sprague Dawley rats underwent 17 days of cocaine or sucrose self-administration, followed by daily treatment with vehicle or RVX-208 (25 mg/kg, i.p.) during a 14-day abstinence period. Next, under extinction conditions, rats in the RVX-208-treated group showed reduced lever pressing compared to vehicle controls, with the effect being more pronounced in males than in females. Sucrose-seeking and open field behavior (distance traveled and time in the center zone) were not significantly affected by RVX-208 treatment. Proteomic analysis of the NAc revealed that RVX-208 modulated several proteins, including those associated with dopamine activity (DRD1 and SLC6A3), transcriptional regulation (NFKB1), glutamate transport (SLC1A2), and ion channel activity (KCNJ10), and many changes were sex-dependent. Collectively, these findings indicate that domain-selective BET inhibition is effective at reducing cocaine-seeking behavior under extinction conditions and point to novel mechanisms that may contribute to its therapeutic effect.