A novel epigenetic brain defense against recurrence of opioid use

Summary: HDAC5, the “epigenetic” enzyme, plays a key role in limiting opioid-associated memories and drug-seeking behaviors after drug abstinence in rats. The findings open a new avenue for the treatment of opioid addiction.

Source: Medical University of South Carolina

Substance use disorder (SUD) is an extremely difficult disorder to overcome, and many people with SUD return to regular use after repeated attempts to quit.

A return to regular drug use can be caused by the body’s physical dependence on drugs as well as experiences associated with previous drug use. It is unclear exactly how these drug associations form in the brain and how they trigger a return to drug use.

“Individuals make lasting associations between the euphoric drug experience and the people, places, and things associated with drug use,” said Christopher Cowan, Ph.D. professor in the University’s Department of Neuroscience. Medical School of South Carolina (MUSC) and member of the Scientific Council of the Brain and Behavior Research Foundation.

Cowan and his team report in the Proceedings of the National Academy of Sciences that an enzyme known as histone deacetylase 5, or HDAC5, plays an important role in limiting heroin-associated memories and drug-seeking behavior after a period of abstinence in rats.

The study reveals HDAC5 as a target of interest in the treatment of vulnerability to return to drug use in opioid use disorders.

HDAC5 is an “epigenetic” enzyme, which means it can influence the expression of many different genes. HDAC5 is active in the brain and has previously been associated with the resumption of cocaine use after a period of abstinence.

“In a previous study, we showed that HDAC5 is regulated by cocaine and reduces the impact of substance use triggers following cocaine use,” Cowan said. “In the new study, we wanted to know why HDAC5 had these effects and whether they were specific to cocaine or perhaps generalizable to other classes of addictive drugs, such as opioids.”

Cowan examined drug-seeking behaviors by modeling a return to opioid use in rats after a period of abstinence from self-administration of heroin, a commonly used opioid drug.

First, the rats were given the opportunity to self-administer heroin by pressing a lever. At the same time, they were presented with visual and aural cues that they associated with their heroin use.

Then, after 2 to 3 weeks of daily heroin consumption, the rats went through a week of abstinence before being placed back in the environment where they had previously consumed heroin. This drug-associated “place” triggered the lever press, or heroin search, but in this case, no heroin was delivered.

Later, drug-seeking behavior was stimulated in rats by exposing them to visual and audible cues formerly linked to their heroin use.

Finally, the rats were given a small dose of heroin to remind them of the drug sensation, and again this stimulated vigorous heroin seeking.

“By seeing how many times the rats pressed the lever without taking drugs, we can measure the strength of the drug-use context, drug-associated memory cues, or re-exposure to the physiological effects of the drug to promote return to heroin use,” Cowan explained.

To see how HDAC5 controlled drug-seeking behavior after a period of abstinence, Cowan’s lab used a molecular trick to increase or decrease levels of HDAC5 in the nucleus, or DNA-containing site, of their cells. targeted brains.

Rats with lower HDAC5 showed increased heroin seeking behavior when exposed to triggers, while rats with higher HDAC5 showed reduced heroin seeking behavior. This discovery showed that the epigenetic enzyme HDAC5 plays a critical role in modulating the strength of drug-associated memories and in preventing a relapse into drug use.

“We found that HDAC5 limits heroin-associated cues and antagonizes the powerful nature of these drug cues to trigger drug-seeking behavior,” Cowan said. “This suggests that, in the brain, HDAC5 functions to influence the formation and strength of those drug memories that may promote a return to drug use.”

To ensure that their findings were specific to drug-seeking behavior and not just general reward-seeking, Cowan’s lab repeated the same experiment but used sucrose instead of heroin. Sucrose is a simple sugar that rats like to consume and serves as a natural reward.

“There was absolutely no effect of HDAC5 on sucrose-seeking behavior,” Cowan said. “Thus, it appears that addictive drugs, such as cocaine and heroin, engage HDAC5 in a way that is separate from our natural process of learning and memorizing rewards.”

This shows a medium spiny neuron in the nec
Wild-type HDAC5 (red) located in the cytoplasm of a medium spiny neuron of the rat nucleus accumbens. Credit: Medical University of South Carolina, Dr. Christopher Cowan

After observing the effects of HDAC5 on drug-seeking behavior, Cowan’s lab investigated which genes HDAC5 actually controls.

“We found hundreds of genes affected by HDAC5,” Cowan said. “But a large number of genes are linked to ion channels that influence the excitability of neuronal cells in the brain.”

Rats with higher levels of HDAC5 had significantly less excitable neurons than those with low HDAC5, showing that the enzyme has a suppressive effect.

“Suppression of HDAC5 triggering is likely a key underlying mechanism controlling the formation and strength of drug-associated memories,” Cowan said.

With a better understanding at the molecular level of drug addiction and return to drug use, scientists and physicians can develop targeted therapies to treat SUD. Future studies in Cowan’s lab aim to leverage HDAC5 to make the road to recovery less difficult.

“We discovered a mechanism in the brain that controls the formation and maintenance of really potent and long-lasting drug associations,” Cowan said. “We want to translate these findings into the clinic and help people with substance use disorders by reducing their vulnerability to resuming regular drug use.”

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About this epigenetics and opioid addiction research news

Author: Press office
Source: Medical University of South Carolina
Contact: Press Office – Medical University of South Carolina
Picture: Image is in public domain

Original research: Access closed.
“Epigenetic function during heroin self-administration controls future behavior associated with relapse in a cell type-specific manner” by Ethan M. Anderson et al. PNAS


Abstract

Epigenetic function during heroin self-administration controls behavior associated with future relapses in a cell type-specific manner

Opioid use produces long-lasting associations between drug reinforcement/euphoria and discrete or diffuse cues in the drug use environment. These powerful associations can trigger relapse in people recovering from opioid use disorder (OUD).

Here, we sought to determine whether the epigenetic enzyme histone deacetylase 5 (HDAC5) regulates relapse-associated behavior in an animal model of OUD.

We examined the effects of the nucleus accumbens (NAc) HDAC5 on heroin and sucrose seeking behaviors using operant self-administration paradigms. We used cre-dependent virus-mediated approaches to study the cell type-specific effects of HDAC5 on heroin-seeking behavior, gene expression, and synaptic and cellular physiology of the medium spiny neuron (MSN).

We found that NAc HDAC5 functions during the acquisition phase of heroin self-administration to limit future behaviors associated with relapses. Additionally, overexpression of HDAC5 in the NAc suppressed context-associated and restored heroin-seeking behaviors, but did not alter sucrose-seeking.

We also found that HDAC5 functions in MSNs expressing the dopamine D1 receptor to suppress cue-induced heroin seeking, and in MSNs expressing the dopamine D2 receptor to suppress cue-initiated heroin seeking. dope.

By evaluating cell type-specific transcriptomics, we found that HDAC5 reduced the expression of several ion transport genes in D1 and D2 MSNs. Consistent with this observation, HDAC5 also produced firing rate depression in both MSN classes.

These results revealed roles for HDAC5 during active heroin use in MSN D1 and D2 to limit distinct triggers of drug-seeking behavior.

Together, our results suggest that HDAC5 may limit vulnerability to relapse through regulation of ion channel gene expression and suppression of MSN firing rates during active heroin use.

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