ArticleBiological psychiatry2025
Epigenetic Control of an Auxiliary Subunit of Voltage-Gated Sodium Channels Regulates the Strength of Drug-Cue Associations and Relapse-Like Cocaine Seeking.
Article in Biological psychiatry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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Who cites it
4 citing papers in PubMed.
- Histone Deacetylase 5 in Prelimbic Prefrontal Cortex Limits Context-Associated Cocaine Seeking.Biological psychiatry · 2026Article
- Age-dependent transcriptomic effects of morphine in the frontal cortex of female mice.Neuropharmacology · 2026Article
- Renewal and reacquisition of substance-associated relapse.Frontiers in psychology · 2026Review
- Cocaine sensitization and accumbens shell plasticity depend on biological sex and gonadal hormones in C57BL/6J mice.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
13 authors.
Funding
Abstract
backgroundRepeated use of addictive drugs produces long-lasting and prepotent drug-cue associations that increase vulnerability for relapse in individuals with a substance use disorder. Epigenetic factors, such as HDAC5 (histone deacetylase 5), play a key role in regulating the formation of drug-cue associations, but the underlying mechanisms remain unclear.
methodsWe used a combination of molecular biology, cultured cells, tandem mass spectrometry, deacetylase activity measurements, co-immunoprecipitation, and molecular dynamics simulations to assess HDAC5 structure-activity relationships. In male and female Long Evans rats, we used viral-mediated expression of HDAC5 mutants in the nucleus accumbens (NAc) to test effects on cocaine intravenous self-administration and cue-reinstated cocaine seeking. We also used in silico analysis of single-nucleus RNA sequencing data, quantitative reverse transcriptase-polymerase chain reaction, viral-mediated expression of Scn4b short hairpin RNA, patch-clamp electrophysiology, and rat cocaine or sucrose SA to assess Scn4b's effects on NAc intrinsic excitability and cued reward seeking.
resultsWe discovered that 2 conserved cysteines located near HDAC5's catalytic domain were required for its intrinsic deacetylase activity and that HDAC5's deacetylase activity was required in NAc medium spiny neurons (MSNs) to limit relapse-like cue-reinstated cocaine seeking. Moreover, we found that HDAC5 limited cocaine-seeking, but not sucrose-seeking, behavior by reducing NAc MSN intrinsic excitability through the deacetylase-dependent repression of Scn4b, which codes for an auxiliary subunit of voltage-gated sodium channels.
conclusionsOur findings suggest that HDAC5's control of NAc Scn4b expression governs the formation of cocaine-cue, but not sucrose-cue, associations through modulation of NAc MSN intrinsic excitability and drug-induced NAc plasticity mechanisms.
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