Sarah M Barry, Jessica Huebschman, Derek M Devries, Lauren M McCue, Evgeny Tsvetkov, Rose Marie Akiki, Caroline Limbaker, Ethan M Anderson, Daniel J Wood, Benjamin M Siemsen, Stefano Berto, Michael D Scofield, Makoto Taniguchi, Rachel D Penrod, Christopher W Cowan
{"title":"Histone deacetylase 5 in prelimbic prefrontal cortex limits context-associated cocaine seeking.","authors":"Sarah M Barry, Jessica Huebschman, Derek M Devries, Lauren M McCue, Evgeny Tsvetkov, Rose Marie Akiki, Caroline Limbaker, Ethan M Anderson, Daniel J Wood, Benjamin M Siemsen, Stefano Berto, Michael D Scofield, Makoto Taniguchi, Rachel D Penrod, Christopher W Cowan","doi":"10.1016/j.biopsych.2025.06.027","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Repeated cocaine use produces neuroadaptations that support drug craving and relapse in substance use disorders (SUDs). Powerful associations formed with drug-use environments can promote a return to active drug use in SUD patients, but the molecular mechanisms that control the formation of these prepotent drug-context associations remain unclear.</p><p><strong>Methods: </strong>In an animal model of intravenous cocaine self-administration (SA) model, we used male Sprague-Dawley rats to examine the role of histone deacetylase 5 (HDAC5) in the prelimbic (PrL) and infralimbic (IL) cortices in context-associated drug seeking. To this end, we employed viral molecular tools, chemogenetics, RNA-sequencing, electrophysiology, and immunohistochemistry.</p><p><strong>Results: </strong>In the PrL, reduction of endogenous HDAC5 augmented context-associated, but not cue- or drug prime-reinstated cocaine seeking, whereas overexpression of HDAC5 in PrL, but not IL, reduced context-associated cocaine seeking, but had no effects on sucrose seeking. In contrast, PrL HDAC5 overexpression following acquisition had no effects on future cocaine seeking. We found that HDAC5 and cocaine SA altered expression of numerous PrL genes, including many synapse-associated genes. HDAC5 significantly increased inhibitory synaptic transmission onto PrL deep-layer pyramidal neurons, and reduced the induction of FOS-positive neurons in the cocaine SA environment.</p><p><strong>Conclusions: </strong>Our findings reveal an essential and selective role for PrL HDAC5 to limit associations formed in cocaine, but not sucrose, SA environments, and that it alters the PrL excitatory/inhibitory balance, possibly through epigenetic regulation of synaptic genes. These results further position HDAC5 as a key factor regulating reward-circuit neuroadaptations that underlie common relapse triggers in SUD.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.0000,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biological Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.biopsych.2025.06.027","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Repeated cocaine use produces neuroadaptations that support drug craving and relapse in substance use disorders (SUDs). Powerful associations formed with drug-use environments can promote a return to active drug use in SUD patients, but the molecular mechanisms that control the formation of these prepotent drug-context associations remain unclear.
Methods: In an animal model of intravenous cocaine self-administration (SA) model, we used male Sprague-Dawley rats to examine the role of histone deacetylase 5 (HDAC5) in the prelimbic (PrL) and infralimbic (IL) cortices in context-associated drug seeking. To this end, we employed viral molecular tools, chemogenetics, RNA-sequencing, electrophysiology, and immunohistochemistry.
Results: In the PrL, reduction of endogenous HDAC5 augmented context-associated, but not cue- or drug prime-reinstated cocaine seeking, whereas overexpression of HDAC5 in PrL, but not IL, reduced context-associated cocaine seeking, but had no effects on sucrose seeking. In contrast, PrL HDAC5 overexpression following acquisition had no effects on future cocaine seeking. We found that HDAC5 and cocaine SA altered expression of numerous PrL genes, including many synapse-associated genes. HDAC5 significantly increased inhibitory synaptic transmission onto PrL deep-layer pyramidal neurons, and reduced the induction of FOS-positive neurons in the cocaine SA environment.
Conclusions: Our findings reveal an essential and selective role for PrL HDAC5 to limit associations formed in cocaine, but not sucrose, SA environments, and that it alters the PrL excitatory/inhibitory balance, possibly through epigenetic regulation of synaptic genes. These results further position HDAC5 as a key factor regulating reward-circuit neuroadaptations that underlie common relapse triggers in SUD.
期刊介绍:
Biological Psychiatry is an official journal of the Society of Biological Psychiatry and was established in 1969. It is the first journal in the Biological Psychiatry family, which also includes Biological Psychiatry: Cognitive Neuroscience and Neuroimaging and Biological Psychiatry: Global Open Science. The Society's main goal is to promote excellence in scientific research and education in the fields related to the nature, causes, mechanisms, and treatments of disorders pertaining to thought, emotion, and behavior. To fulfill this mission, Biological Psychiatry publishes peer-reviewed, rapid-publication articles that present new findings from original basic, translational, and clinical mechanistic research, ultimately advancing our understanding of psychiatric disorders and their treatment. The journal also encourages the submission of reviews and commentaries on current research and topics of interest.