Dopamine isn’t just the “feel good” neurotransmitter. According to a new study from the Mount Sinai School of Medicine, it is also an epigenetic regulator. Through a process called dopaminylation, it binds to chromatin, altering gene expression in brain cells and effectively rewiring the brain’s reward circuitry. This surprising finding emerged from a study of cocaine addiction, but it may be relevant to the abuse of drugs other than cocaine, as well as to reward-seeking behavior generally.

Specifically, a Mount Sinai research team led by Ian Maze, PhD, associate professor of neuroscience and pharmacological sciences, found that a protein called transglutaminase 2 can directly attach dopamine molecules to histones, the proteins that form spool-like complexes around which DNA is wound.

If histone modification, DNA spooling, and gene expression are altered due to environmental influences, such as chronic cocaine exposure, behaviors may change, including behaviors such as cocaine seeking.

This possibility was explored in a paper (“Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking”) contributed by Maze’s team to Science. The paper, which appeared April 10, describes how histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain.

“Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the ventral tegmental area (VTA),” the article’s authors wrote. “By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior.”

Accumulation of H3Q5dop in the VTA can, in effect, hijack the reward circuitry, making it difficult to distinguish between good and maladaptive behavior. However, reducing H3Q5dop in rats programmed to undergo withdrawal from cocaine significantly reversed cocaine-mediated gene expression changes and reduced cocaine-seeking behavior.

“Our study provides the first evidence of how dopamine can directly impact drug-induced gene expression abnormalities and subsequent relapse behavior,” asserted Maze. “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. This biochemical process significantly affects cocaine vulnerability and relapse when perturbed by drugs of abuse.”

Dopamine is better known as a chemical that ferries information between neurons. The brain releases it when we eat food that we crave or while we have sex, contributing to feelings of pleasure and satisfaction as part of the natural reward system. Dopamine boosts mood, motivation, and attention, and helps regulate movement, learning, and emotional responses. Dopamine also enables us not only to see rewards but to take action to move toward them.

Now it has emerged that dopamine also works as an epigenetic regulator in VTA neurons during periods of drug seeking. Through the newfound mechanism of dopaminylation, dopamine may reinforce drug addiction behaviors.

“The question that has always challenged neuroscientists is, what are the underlying molecular phenomena that drive increased vulnerability to drug relapse in people,” said Ashley Lepack, PhD, a researcher in Maze’s lab and the first author of the current study. “Our research is shedding valuable light on this area by identifying histone dopaminylation as a new, neurotransmission-independent role for dopamine that hasn’t been implicated before in brain pathology.”

“We believe these findings represent a paradigm shift in how we think of dopamine, not just in the context of drug abuse, but also potentially in other reward-related behaviors and disorders, as well as in neurodegenerative diseases like Parkinson’s, where dopamine neurons are dying,” added Maze. “In this case, the question becomes, ‘could this neuronal death be due, in part, to aberrant dopaminylation of histone proteins?’”

In a study published last year, Maze and his team found that another neurotransmitter, serotonin, a chemical involved in the regulation of mood, acts in a similar way as dopamine on gene expression inside brain cells.

“When we observed this unique signaling mechanism with serotonin,” recalled Maze, “we decided to look at other neurotransmitters, particularly dopamine, and found that it could also undergo this type of chemical modification on the same histone protein.”

Early-stage work with human postmortem tissues has demonstrated to Maze that strong parallels may well exist, but that basic questions around biochemical function still remain before human trials can begin.

“From a therapeutic standpoint, we’ve started to identify from rodent models the mechanisms that can actually reverse aberrant and addictive behaviors,” declared Maze, “and that knowledge could be vital to moving this novel research into the clinic.”