Study finds new epigenetic brain defense helps to overcome opioid use

Uncertainty still exists over how these drug associations are created in the brain and how they lead to a relapse.

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

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

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

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 formerly used heroin. This drug-associated “place” triggered the pressing of the lever, or heroin seeking, but in this case no heroin was delivered.

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

“By seeing how many times the rats press the lever while not getting the drug, we can measure the strength of the drug-use context, the drug-associated memory cues or the re-exposure to physiological drug effects to promote return to heroin use,” explained Cowan.

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

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

“There was absolutely no effect of HDAC5 on sucrose-seeking behavior,” said Cowan. “So, it seems that addictive drugs, like cocaine and heroin, are engaging HDAC5 in a way that is separate from our natural reward learning and memory process.”

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

“The firing suppression from HDAC5 is likely a key underlying mechanism controlling the formation and strength of drug-associated memories,” said Cowan.

“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.”