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Dopamine modification on chromatin linked to addiction

In chromatin, DNA (yellow) is wound around histone proteins (blue). Chemical changes to histones can affect the way the genes in DNA are expressed. selvanegra / iStock / Getty Images Plus

Drug addiction is a chronic disease. It’s characterized by a person seeking out a drug and using it compulsively despite harmful consequences. At first, the decision to take drugs is voluntary for most people. But repeated drug use can lead to brain changes that interfere with your ability to resist taking them.

Most drugs affect the brain's reward circuit by flooding it with a chemical messenger called dopamine. Surges of dopamine, sent from a brain region called the ventral tegmental area, reinforce drug-taking behavior, leading people to take it again and again.

Many people relapse, or return to drug use after an attempt to stop. Changes in gene expression—how genes are turned on and off—are believed to cause people to become more vulnerable to relapse over the long term. What leads to these gene expression changes is unknown.

Chemical modifications of chromatin—the structure that DNA and proteins called histones are packed into to form chromosomes—can affect gene expression. Previous studies have found that serotonin, a chemical messenger similar to dopamine, can modify histones and cause changes in gene expression.

To investigate whether dopamine can also modify histones and alter gene expression related to relapse behaviors, a research team led by Dr. Ian Maze at the Icahn School of Medicine at Mount Sinai carried out a study on human post-mortem brain tissue and in genetically engineered rats. The work was funded in part by NIH’s National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), and National Institute of Neurological Disorders and Stroke (NINDS). Results were published on April 10, 2020, in Science.

The team first confirmed in the lab that dopamine could be chemically linked to histones. They named the modification “histone dopaminylation.” They next examined histone dopaminylation levels in postmortem brain tissue from people with cocaine addiction and healthy controls. Levels of dopaminylation were lower in the samples from cocaine users.

To investigate histone dopaminylation following withdrawal from the drug, the researchers trained rats to self-administer cocaine over 10 days. Some were given restricted access to the drug for one hour and others were given extended access to the drug for six hours. Animals given extended access, but not those with restricted access, gradually increased their drug intake across training sessions.

Rats with extended access showed decreased histone dopaminylation at first, similar to the human postmortem brain results. Over a month of cocaine withdrawal, however, histone dopaminylation steadily increased, becoming higher than controls after 30 days. This increase was specific to rats given extended access and was not seen in the rats with restricted access or in the controls trained to self-administer food.

The team then genetically blocked histone dopaminylation in rats after the self-administration training. Reducing histone dopaminylation lowered dopamine release in the brain’s reward center, cocaine-mediated gene expression changes, and cocaine-seeking behavior in rats undergoing withdrawal.

“Beyond transmission of signals between neurons in the brain, we have found that dopamine can be chemically attached to histone proteins, which causes cells to switch different genes on and off, affecting regions of the brain that are involved in motivation and reward behavior,” Maze says. “From a therapeutic standpoint, we've started to identify from rodent models the mechanisms that can actually reverse aberrant and addictive behaviors, and that knowledge could be vital to moving this novel research into the clinic.”

—by Tianna Hicklin, Ph.D.