Brain Enzyme Limits Risk of Drug Relapse – Neuroscience News

Summary: New research reveals that the enzyme HDAC5 plays a critical role in suppressing a gene (Scn4b) that regulates brain activity associated with drug-related memories, which are central to relapse in substance use disorders (SUDs). By limiting expression of Scn4b, HDAC5 reduces the excitability of neurons in the brain’s reward system, weakening the formation of powerful drug-environment associations.

The study also found that SCN4B influences cocaine relapse-like behavior without affecting natural reward-seeking, highlighting it as a potential drug-specific therapeutic target. These findings offer a deeper understanding of addiction’s biological roots and open new avenues for relapse prevention strategies.

Key Facts:

• HDAC5 Role: HDAC5 suppresses the gene Scn4b, limiting neuron activity that underlies relapse-triggering drug memories.
• Drug-Specific Impact: SCN4B influences cocaine seeking without affecting natural rewards like sucrose.
• New Treatment Target: These mechanisms identify SCN4B as a potential target for relapse-specific addiction therapies.

Source: Elsevier

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, 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.”

About this addiction and genetics research news

Author: Eileen Leahy
Source: Elsevier
Contact: Eileen Leahy – Elsevier
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Epigenetic control of an auxiliary subunit of voltage-gated sodium channels regulates the strength of drug-cue associations and relapse-like cocaine seeking” by Christopher W. Cowan et al. Biological Psychiatry

Abstract

Epigenetic control of an auxiliary subunit of voltage-gated sodium channels regulates the strength of drug-cue associations and relapse-like cocaine seeking

Background

Repeated use of illicit drugs produces long-lasting and prepotent drug-cue associations that increase vulnerability for relapse in individuals with a substance use disorder. Epigenetic factors, like histone deacetylase 5 (HDAC5), play a key role in regulating the formation of drug-cue associations, but the underlying mechanisms remain unclear.

Methods

We 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 nucleus accumbens (NAc) to test effects on cocaine intravenous self-administration (SA) and cue-reinstated cocaine seeking.

We also used in silico analysis of single-nucleus RNA sequencing data, quantitative RT-PCR, viral-mediated expression of Scn4b shRNA, patch-clamp electrophysiology, and rat cocaine or sucrose SA to assess Scn4b’s effects on NAc intrinsic excitability and cued reward seeking.

Results

We discovered that two 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 to limit relapse-like cue-reinstated cocaine seeking.

Moreover, we found that HDAC5 limited cocaine, 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.

Conclusions

Our 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.