The Epigenetic Link too Addiction

Substance use disorders (SUDs) continue to pose a meaningful challenge in the United States and worldwide. Despite ongoing efforts, rates of SUDs have remained relatively stable, underscoring the need for innovative treatment and prevention strategies. New research sheds light on the biological underpinnings of addiction, focusing on epigenetic mechanisms that influence drug-related memories [[1]], [[2]], [[3]].

A recent study published in Biological Psychiatry details how the epigenetic enzyme histone deacetylase 5 (HDAC5) limits the expression of the gene Scn4b. This regulation impacts neuronal activity and, consequently, the formation of strong drug-related memories that can trigger relapse.

HDAC5 and SCN4B: A New Molecular Target

the research highlights HDAC5 as a critical player in modulating neuronal excitability within the nucleus accumbens, a brain region closely associated with SUDs and reward-related behavior. Christopher W. Cowan, PhD, co-lead investigator from the medical University of South Carolina, explained:

In this study, we discovered that a critical epigenetic enzyme HDAC5 functions to limit the expression of Scn4b, wich 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.
Christopher W. Cowan,PhD,Medical University of South Carolina

This discovery suggests that targeting HDAC5 could offer a novel approach to developing treatments for SUDs.

The Role of SCN4B in Relapse

The study’s findings reveal that SCN4B, a sodium channel auxiliary protein, selectively limits relapse-like cocaine seeking without affecting the seeking of natural rewards like sucrose. This specificity suggests that SCN4B governs a form of drug-specific plasticity.

Daniel J. Wood, MD, PhD candidate and co-lead investigator, emphasized the importance of this finding:

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.
Daniel J.Wood, MD, PhD, Medical University of south Carolina

Expert Commentary

John Krystal, MD, Editor of Biological Psychiatry, provided further insight into the meaning of these findings:

People say that once you have experienced compulsive substance use, yoru 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.
John Krystal, MD, Editor of Biological psychiatry

Dr. Krystal also noted the potential for new treatments:

The deeper neuroscience probes into addiction, the more we uncover essential 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.
John Krystal, MD, Editor of Biological Psychiatry

Research Methods

the study employed a wide range of research techniques, including:

• Tandem mass spectrometry
• Enzymatic activity assays
• Computational modeling
• Quantitative mRNA analysis
• patch-clamp electrophysiology
• Rat cocaine and sucrose self-management

This multi-faceted approach allowed the investigators to gain a comprehensive understanding of the epigenetic mechanisms at play.

looking Ahead

The identification of HDAC5 and SCN4B as key regulators in drug-related memories opens new avenues for developing targeted therapies for SUDs. Further research is needed to fully elucidate the mechanisms involved and to translate these findings into effective treatments.