A new epigenetic brain defense against recurrence of opioid use

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

Source: Medical University of South Carolina

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

A return to regular drug use can be triggered by the body’s physical dependence on the drug, as well as experiences related to previous drug use. Exactly how these drug associations are formed in the brain and how they trigger a return to drug use remains unclear.

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

Cowan and his team report in the Procedures 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 that HDAC5 is an interesting target in the treatment of the vulnerability to return to drug use in opioid use disorders.

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

“In a previous study, we showed that HDAC5 is regulated by cocaine and that it reduces the impact of substance use triggers following cocaine use,” said Cowan. “In the new study, we wanted to learn 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 investigated drug-seeking behavior 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, rats were given the chance to self-administer heroin by pressing a lever. At the same time, they were shown visual and audio cues that they associated with their heroin use.

Then, after 2-3 weeks of daily heroin use, the rats went through a week of abstinence before being placed back in the environment where they used heroin before. This drug-related “place” caused the lever-press or heroin-searching, but no heroin was delivered in this case.

Later, drug-seeking behavior was stimulated in the rats by exposing them to the visual and audio cues previously associated with their heroin use.

Finally, the rats were given a small dose of heroin to remind them of the feeling of the drug, again stimulating a vigorous search for heroin.

“By seeing how often the rats hit the lever while not getting the drug, we can measure the strength of the drug use context, the drug-related memory cues, or the re-exposure to physiological drug effects to promote a return to heroin use,” explains Cowan.

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

Rats with a lower HDAC5 showed more heroin-seeking behavior when exposed to triggers, while rats with a higher HDAC5 showed less heroin-seeking behavior. This finding showed that the epigenetic enzyme HDAC5 plays a critical role in modulating the strength of drug-related memories and preventing a return to drug use.

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

To ensure their findings were specific to drug seeking 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. “So it appears that addictive drugs, such as cocaine and heroin, engage HDAC5 in a way that is separate from our natural reward learning and memory process.”

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

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

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

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

“The suppression of HDAC5 firing is likely an important underlying mechanism that controls 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 clinicians can develop targeted therapies to treat addiction. Future studies in Cowan’s lab aim to use HDAC5 to make the road to recovery less challenging.

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

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About this news about epigenetics and opioid addiction research

Author: Press Office
Source: Medical University of South Carolina
Contact: Press Service – Medical University of South Carolina
Image: The image is in the public domain

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


Abstract

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

Opioid use produces persistent associations between drug enhancement/euphoria and discrete or diffuse cues in the drug-using environment. These powerful associations can trigger relapse in individuals recovering from opioid use disorder (OLD).

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

We found that NAc HDAC5 functions during the acquisition phase of heroin self-administration to limit future relapse-associated behavior. In addition, overexpressing HDAC5 in the NAc suppressed context-associated and restored heroin seeking, but did not alter sucrose seeking.

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

In assessing cell type-specific transcriptomics, we found that HDAC5 reduced the expression of multiple ion transporter genes in both D1 and D2 MSNs. Consistent with this observation, HDAC5 also caused a decrease in rate of fire in both MSN classes.

These findings revealed roles for HDAC5 during active heroin use in both D1 and D2 MSNs to limit various triggers of drug-seeking behavior.

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

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