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Epigenetics and Addiction: New Study Reveals How HDAC5 Regulates Opioid Relapse

In a recent study, published in PNAS, researchers have identified an epigenetic enzyme, histone deacetylase 5 (HDAC5), that plays a crucial role in regulating relapse-associated behaviour in rats with opioid use disorder (OUD). By modulating drug-associated memories, HDAC5 could be a key target for developing effective treatments for OUD and other substance use disorders.

The opioid epidemic

The opioid epidemic is a public health crisis that has had devastating consequences in the United States and around the world. Opioid use disorder (OUD) is a chronic, relapsing disease that can lead to long-term health problems, including overdose and death. One of the key challenges in treating OUD is understanding how active opioid use creates future relapse vulnerability.

HDAC5 is an “epigenetic” enzyme that has been shown to regulate gene expression and in previous studies has shown to be associated with resumed cocaine use after a period of abstinence. “In a prior study, we showed that HDAC5 is regulated by cocaine, and it reduces the impact of substance use triggers following cocaine use,” said Christopher Cowan, an author of the study. “In this new study, we wanted to learn why HDAC5 had these effects and if they were specific to cocaine or perhaps generalizable to other classes of addictive drugs, like opioids.”

Chasing the heroin

This recent study has shown that HDAC5 plays a critical role in regulating relapse-associated behaviour in a rodent model of OUD. The researchers first allowed the rats to self-administer heroin by pressing a lever while being exposed to visual and audio cues associated with the drug. After two to three weeks of daily heroin use, the rats underwent a week of abstinence before being placed back in the environment where they formerly used heroin. This drug-associated “place” triggered heroin-seeking behaviour, but no heroin was delivered.

The researchers then stimulated drug-seeking behaviour in the rats by exposing them to the visual and audio cues formerly linked to their heroin use. Finally, the rats were given a small dose of heroin to remind them of the feeling of the drug, which stimulated vigorous heroin-seeking.

To investigate how HDAC5, an epigenetic enzyme, controlled drug-seeking behaviour after a period of abstinence, the researchers either increased or decreased HDAC5 levels in specific neurons. Rats with lower HDAC5 showed enhanced heroin-seeking behaviour when exposed to triggers, while rats with higher HDAC5 showed reduced heroin-seeking behaviour. This finding suggests that HDAC5 plays a critical role in modulating the power of drug-associated memories and preventing a return to drug use.

Ratting Out Addiction

To ensure that their findings were specific to drug-seeking behaviour, the researchers repeated the same experiment using sucrose instead of heroin. Sucrose is a simple sugar that rats enjoy consuming and serves as a natural reward. However, the researchers found no effect of HDAC5 on sucrose-seeking behaviour. This result suggests that addictive drugs, like cocaine and heroin, engage HDAC5 in a way that is separate from our natural reward learning and memory process.

To further investigate the effects of HDAC5 on drug-associated memories, Cowan’s lab analyzed the genes controlled by the enzyme. They found that HDAC5 affected hundreds of genes, many of which were linked to ion channels that influenced the excitability of neuronal cells in the brain. Rats with higher levels of HDAC5 had less excitable neurons, indicating that the enzyme has a suppressive effect. “The firing suppression from HDAC5 is likely a key underlying mechanism controlling the formation and strength of drug-associated memories,” said Cowan.

Regulating relapse

This study sheds light on the underlying causes of addiction and provides valuable insights into how relapse-associated behaviour can be regulated through epigenetic mechanisms. Understanding the role of enzymes like HDAC5 in addictive behaviour is critical to developing effective treatments for OUD and other substance use disorders. By identifying the specific genes and neural pathways involved in drug-associated memories, researchers can develop targeted therapies that address the root causes of addiction and prevent relapse. “We have uncovered a mechanism in the brain that is controlling the formation and maintenance of really powerful and enduring drug-cue associations,” said Cowan. “We want to translate these findings to the clinic and help individuals with substance use disorder by reducing vulnerability to return to regular drug use.”

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