New Drug Target for Opiate Use Disorder Discovered

A new study provides the first direct evidence of opiate-related epigenetic alterations in the brain and points to a potential new drug target for opiate use disorder.

Investigators at the Icahn School of Medicine at Mount Sinai in New York City found that heroin use is associated with excessive histone acetylation, an epigenetic process that regulates gene expression.

"The study suggests that developing medications that target specific epigenetic mechanisms could be potential treatments for heroin abuse," study chief Yasmin Hurd, PhD, professor of psychiatry and neuroscience, told Medscape Medical News.

Dr Yasmin Hurd

"Offering nonopioid medications for opioid use disorders has significant implications, since a goal is to reduce the exposure of such patients to opioid treatments," added Dr Hurd, who is also the director of the Center for Addictive Disorders at the Mount Sinai Behavioral Health System.

The study was published online in the April 1 issue of Biological Psychiatry.

No Serious Side Effects

To study the molecular underpinnings of heroin addiction, the researchers focused on the striatum, which is implicated in drug addiction. Studying postmortem human striatal tissue from 48 heroin users and 37 control individuals, they found changes in acetylation at genes that regulate the function of the neurotransmitter glutamate, which regulates the drug reward system and controls drug-seeking behavior.

Specifically, the researchers identified changes at the glutamate receptor gene GRIA1, which has previously been implicated in drug use.

The researchers observed the same histone hyperacetylation alterations in a rat model of heroin addiction. Using this translational model, they showed that treatment with the bromodomain inhibitor JQ1, which blocks the functional readout of acetylated lysines, reduced heroin self-administration and drug-seeking behavior after abstinence from heroin.

"Importantly, JQ1 potently reversed addiction behavior during the maintenance phase and during reinstatement after abstinence in our model, suggesting that this drug might hold clinical promise for the treatment of long-term human heroin users," the researchers write.

"Importantly, phase 1 clinical trials using JQ1 are ongoing in patients with cancer and serious side effects have not yet been reported, which would set the stage for future clinical addiction studies," they add.

Dr Hurd said a number of research projects are being considered, "such as trying to understand the full neurobiological actions of JQ1 that leads to its effects to reduce opioid intake and to determine whether other compounds with a similar profile to JQ1 can have similar effects on heroin self-administration and relapse behavior."

The study was supported by grants from the National Institutes of Health and the US Department of Veterans Affairs. The authors have disclosed on relevant financial relationships.

Biol Psychiatry. 2017;81:585-594. Abstract

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