{"doi":"10.1073/pnas.2210953120","title":"Epigenetic function during heroin self-administration controls future relapse-associated behavior in a cell type-specific manner","abstract":"Opioid use produces enduring associations between drug reinforcement/euphoria and discreet or diffuse cues in the drug-taking environment. These powerful associations can trigger relapse in individuals recovering from opioid use disorder (OUD). Here, we sought to determine whether the epigenetic enzyme, histone deacetylase 5 (HDAC5), regulates relapse-associated behavior in an animal model of OUD. We examined the effects of nucleus accumbens (NAc) HDAC5 on both heroin- and sucrose-seeking behaviors using operant self-administration paradigms. We utilized cre-dependent viral-mediated approaches to investigate the cell-type-specific effects of HDAC5 on heroin-seeking behavior, gene expression, and medium spiny neuron (MSN) cell and synaptic physiology. We found that NAc HDAC5 functions during the acquisition phase of heroin self-administration to limit future relapse-associated behavior. Moreover, overexpressing HDAC5 in the NAc suppressed context-associated and reinstated heroin-seeking behaviors, but it did not alter sucrose seeking. We also found that HDAC5 functions within dopamine D1 receptor-expressing MSNs to suppress cue-induced heroin seeking, and within dopamine D2 receptor-expressing MSNs to suppress drug-primed heroin seeking. Assessing cell-type-specific transcriptomics, we found that HDAC5 reduced expression of multiple ion transport genes in both D1- and D2-MSNs. Consistent with this observation, HDAC5 also produced firing rate depression in both MSN classes. These findings revealed roles for HDAC5 during active heroin use in both D1- and D2-MSNs to limit distinct triggers of drug-seeking behavior. Together, our results suggest that HDAC5 might limit relapse vulnerability through regulation of ion channel gene expression and suppression of MSN firing rates during active heroin use.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":335057,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":311331,"name":"Tsvetkov Ea","orcid":"0000-0002-6784-0907","position":1,"is_corresponding":false},{"id":1064017,"name":"Allison Galante","orcid":"0000-0002-6201-3945","position":2,"is_corresponding":false},{"id":1064018,"name":"Derek M. DeVries","orcid":"0000-0002-1518-1196","position":3,"is_corresponding":false},{"id":1064019,"name":"Lauren M McCue","orcid":"0000-0001-9936-1591","position":4,"is_corresponding":false},{"id":576248,"name":"D.J. Wood","orcid":"0000-0002-1841-3706","position":5,"is_corresponding":false},{"id":1064020,"name":"Sarah M. Barry","orcid":"0000-0001-8188-2153","position":6,"is_corresponding":false},{"id":311328,"name":"Stefano Berto","orcid":"0000-0001-9028-9458","position":7,"is_corresponding":false},{"id":820081,"name":"Antonieta Lavı́n","orcid":"0000-0002-0056-7862","position":8,"is_corresponding":false},{"id":819868,"name":"Makoto Taniguchi","orcid":"0000-0001-6356-2463","position":9,"is_corresponding":false},{"id":287641,"name":"Christopher W. Cowan","orcid":"0000-0001-5472-3296","position":10,"is_corresponding":false},{"id":481501,"name":"Ethan M. Anderson","orcid":"0000-0002-4021-6741","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T01:09:53.742667Z","pmid":"36745812","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}