Research on the biological basis of addiction published in Biological Psychiatry uncovers the critical role that the HDAC5 enzyme plays in gene expression in the brain's epigenetic mechanisms that influence relapse-related cocaine consumption

Philadelphia, April 10, 2025 – New research on the biological basis of addiction has found that the critical epigenetic enzyme histone deacetylase 5 (HDAC5) limits the expression of the gene Scn4b, regulating neuronal activity and thereby the formation of strong drug-related memories, which can trigger relapse in individuals with substance use disorders (SUDs). The study in Biological Psychiatry, published by Elsevier, detailing these epigenetic mechanisms in the brain, uncovers a new molecular target for the development of novel SUD treatments.

SUDs affect many individuals in the United States directly or indirectly. Drug-related deaths remain at an all-time high in the US and stimulant use specifically is on the rise worldwide. Despite ongoing efforts, rates of SUDs have remained relatively stable over the past three decades, indicating a need for continued focus on treatment and prevention strategies. Understanding the neurological basis of addiction, often considered a complex biobehavioral illness, holds potential for broader insights into human decision-making, motivation, and behavior.

SUDs are characterized by compulsive drug seeking and use despite adverse consequences, and relapse affects a large proportion of individuals with SUD attempting to discontinue drug use. One major contributor to relapse risk is the presence of enduring associations between the primary rewarding effects of the drug and cues in the drug-use environment.

John Krystal, MD, Editor of Biological Psychiatry, comments, "People say that once you have experienced compulsive substance use, your relationship to that substance can never return to the pre-addiction state. How could these long-lasting associations be sustained? One possibility is that there are long-lasting changes in the pattern of gene expression that encode these drug memories and that prevent these memories from weakening. This study points to epigenetic mechanisms, one of the processes regulating gene expression patterns on a long-term basis, as a key regulator of relapse-related cocaine consumption."

Co-lead investigator Christopher W. Cowan, PhD, Department of Neuroscience, Medical University of South Carolina, explains, "In this study, we discovered that a critical epigenetic enzyme HDAC5 functions to limit the expression of Scn4b, which limits the firing of key neurons in the nucleus accumbens, an important brain region linked to SUD and reward-related behavior. Together with our prior work, our findings show that HDAC5 and SCN4B, via regulation of neuronal excitability, selectively limit the formation of powerful and long-lasting links between the drug use environment and the drug use experience that can later serve as triggers of relapse in individuals with a SUD that are attempting to abstain from a return to active drug use."

In a highly collaborative multilevel study, investigators deployed a wide array of research techniques, including tandem mass spectrometry, enzymatic activity assays, computational modeling, quantitative mRNA analysis, patch-clamp electrophysiology, and rat cocaine and sucrose self-administration. One of the most significant results is the new finding that a sodium channel auxiliary protein, SCN4B, functions to limit relapse-like cocaine seeking but without affecting seeking of a natural reward, sucrose. This suggests that SCN4B governs a form of drug-specific plasticity that creates prepotent drug-environment associations that can promote relapse.

Co-lead investigator Daniel J. Wood, MD, PhD candidate, Department of Neuroscience, and Medical Science Training Program, Medical University of South Carolina, notes, "Finding new ways to help people recovering from SUD remain abstinent is as important as ever. The fact that SCN4B is selectively involved in the relapse-like cocaine seeking, but had no effect on sucrose seeking was very surprising to us. SCN4B might be a key puzzle piece toward uncovering drug-induced maladaptive plasticity that drives prepotent drug-environment associations and relapse vulnerability, and it represents a novel therapeutic target for developing treatments that reduce relapse risk in SUD."

Dr. Krystal concludes, "The deeper neuroscience probes into addiction, the more we uncover fundamental molecular processes that drive or constrain drug seeking. This novel mechanism may point to new treatments for cocaine use disorder, for which there are no current pharmacotherapies.”