A study published in Biological Psychiatry by researchers at the Medical University of South Carolina uncovers how a specific brain enzyme, histone deacetylase 5 (HDAC5), acts as a key molecular brake on cocaine craving and relapse. The research zeroes in on how HDAC5 suppresses the brain’s memory of drug-associated cues, a critical driver of relapse in addiction, by regulating the excitability of neurons in the brain's reward circuitry.
The study explores the role of HDAC5 in the nucleus accumbens (NAc), a central hub for motivation and reward processing. Using a combination of gene editing, electrophysiology, and behavioral experiments in rats, the authors showed that HDAC5’s enzymatic activity represses a gene called Scn4b. This gene encodes SCN4B, an auxiliary subunit of sodium channels critical for neuron firing. By repressing Scn4b, HDAC5 dampens the excitability of NAc medium spiny neurons, thereby reducing the power of cocaine-associated cues to trigger relapse-like behavior.
Notably, the effect was drug-specific: reducing SCN4B had no impact on seeking behaviors related to natural rewards like sucrose. This selectivity suggests that SCN4B is part of a drug-specific plasticity mechanism rather than a general reward system.
A major innovation in the study was the dissection of HDAC5’s structure. The team identified two cysteine residues—C696 and C698—essential for its enzymatic function. Mutation of these residues eliminated HDAC5’s ability to suppress drug-seeking without affecting its ability to bind other proteins like HDAC3 or transcription factors like MEF2. This finding was unexpected because HDAC5 had been thought to rely primarily on its role as a scaffold rather than its own enzymatic activity.
Using viral vectors to deliver mutant forms of HDAC5 into the NAc of rats, the researchers found that only versions of HDAC5 with intact enzymatic activity were able to reduce relapse behavior. In contrast, rats expressing enzymatically inactive HDAC5 pressed more for cocaine after abstinence and cue exposure, indicating stronger drug-cue memory.
Further experiments demonstrated that reducing Scn4b expression mimicked the effects of HDAC5 activation—lower neuron excitability and reduced cocaine seeking—highlighting SCN4B as a potential therapeutic target.
The work also sidestepped traditional pathways previously linked to HDAC5, such as MEF2-dependent gene repression. Despite HDAC5’s known interaction with MEF2, cue-triggered cocaine seeking was unaffected by MEF2 knockdown, underscoring the independence of this HDAC5-SCN4B mechanism.
What emerges from this research is a sophisticated picture of how the brain encodes and regulates drug-associated memories at the molecular level. The discovery positions HDAC5 not only as a modulator of gene expression but as a functional enzymatic regulator that sets the tone for neuronal responsiveness to drug cues.
The full article is available via this DOI link: https://doi.org/10.1016/j.biopsych.2025.01.027
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