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After reversing cocaine addiction in mice, University of Maryland researcher turns to opioids

A University of Maryland researcher who successfully, if temporarily, reversed the effects of cocaine addiction in mice is expanding her research into opioid addiction in the hopes of eventually developing a treatment for humans.

Meaghan Creed, an assistant professor of pharmacology at the University of Maryland School of Medicine, used electrical stimulation in the brains of mice coupled with medicine to reverse permanent changes caused by cocaine addiction. The research eventually could lead to development of new treatment options for substance abuse disorders.


An essay Creed wrote on the work, which she conducted with colleagues at the University of Geneva in Switzerland, earned her a $25,000 prize in August from the American Association for the Advancement of Science for illuminating the complex and often poorly understood biology of addiction.

A Canadian who previously did post-doctoral work at the Swiss university, Creed said seeing the extent of opioid addiction in Baltimore helped shape her research interests.


"It was never really on the radar," she said. "And then when I came here, especially to Baltimore, it's the reality. So that was really striking and did kind of change my trajectory a bit."

The nation is in the midst of an epidemic of overdose deaths from opioids, particularly heroin and fentanyl, but also from prescription painkillers such as oxycodone. Opioid overdose deaths have more than quadrupled since 1999, according to the U.S. Centers for Disease Control and Prevention.

In Maryland, fentanyl — a powerful illegal narcotic typically mixed with heroin — contributed to 372 of the 550 drug- and alcohol-related overdoses between January and March of this year. And Baltimore is a battleground, accounting for about a third of those numbers.

As part of her work, Creed is trying to learn more about how drug addiction rewires the brain. Her past research on cocaine addiction in mice showed that addictive agents permanently change brain synapses, which act as "craving messengers."

Better understanding of what's happening in the brain could help researchers hone treatment methods like the one Creed is now looking into for opioid addiction.

Creed's research initially focused on changing brain chemistry using a process called optogenetics — the use of light to selectively control specific groups of neurons in the brain — to reverse symptoms of addiction in rodents.

The process involved introducing light-sensitive proteins into the brains of the mice and using light delivered by an optic fiber to turn on and off very specific areas of their brains. Using optogenetics, Creed was able to harness the neurotransmitter glutamate to reverse the brain changes that happen in addiction. Neurotransmitters are the brain's chemical messengers.

Because optogenetics is not approved for use in humans, the team also tried electrical deep-brain stimulation in an effort to recreate its effects.


Deep-brain stimulation involves placing electrodes into the brain and delivering electrical current to target different areas. It's been used for more than two decades to treat advanced Parkinson's disease and more recently to prevent epilepsy seizures.

For Parkinson's, a surgically implanted neurostimulator device delivers high-frequency electrical stimulation to the parts of the brain that control movement and blocks the abnormal nerve signals that cause tremors.

Creed's research into the way cocaine rewires the brain in Switzerland led her to try using low-frequency stimulation.

Like optogenetics, the deep-brain stimulation activated glutamate, but it also triggered the neurotransmitter dopamine, which appeared to cancel out the glutamate, said Lorenzo Leggio, a National Institutes of Health researcher who is familiar with Creed's work.

Dopamine is a neurotransmitter that helps control the brain's reward and pleasure centers.

"The last piece of the puzzle was to apply deep-brain stimulation with a drug that blocks dopamine, and when she did that she was able to reproduce the same beneficial effects of optogenetics," said Leggio, who is also a clinical investigator with the National Institute on Alcohol Abuse and Alcoholism's Division of Intramural Clinical and Basic Research and the National Institute on Drug Abuse Intramural Research Program.


Creed first tried the drug, called SCH-23390, then recreated the results with a similar drug called Ecopipam.

Mice addicted to cocaine exhibit craving behaviors and react excitedly to stimuli that remind them of cocaine, Creed said. After treating them with the combination of deep-brain stimulation and medication, the mice behaved like mice that had never been exposed to cocaine, she said.

The effect, however, only lasted about a week before the mice returned to their addicted behavior, she said.

While very early in development, this method offers a potential blueprint for correcting neural circuit dysfunction after prolonged use of addictive drugs.

Creed said she thinks her work had promising potential to help humans because deep-brain stimulation already is used to treat Parkinson's disease. However, treatments that work in mice don't always translate to humans, especially with something as complicated and multi-faceted as drug addiction.

So far, her research has only been performed in mice. It needs to be tested in monkeys before it can be tested in humans.


"I think monkey trials are something people really want to see," she said. "I'm very convinced that in mice it works wonderfully, but as you move up the species there's questions. The behavior is more complex."

Deep-brain stimulation is still not well understood, said Leggio, but Creed's research has helped scientists better understand how it may work in the brain.

"Her work is very exciting and very important in shedding light on how deep brain stimulation works," Leggio said. "It's not a full understanding, but her work has been a discovery and an important step forward."

Garret D. Stuber, an associate professor in the departments of psychiatry and cell biology and physiology at the University of North Carolina at Chapel Hill, said there was a lot of interest among scientists in using brain stimulation techniques on addiction and mood disorders.

"It's an interesting approach I think not many people in the field have really used," Stuber said. "It's pretty novel and important. It opens up a new way to think about doing these experiments."

Creed said she also wants to know whether some people are predisposed genetically to addiction and how addiction induces depression-like symptoms after the user stops taking the drug, which she thinks is a primary reason people have a hard time quitting.


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"Is there something different in the neurocircuits of different patients before they even see drugs that predisposes them?" she said. "That was my main line of research before I moved to Baltimore, and then actually being in Baltimore and seeing the priorities, it's become a bit more shifted toward the opiate side."

Creed said other researchers have identified possible genetic links that predispose people to mood disorders such as bipolar disease that involve dopamine and that she believes could be linked to addiction.

Mice with the predisposition to mood disorders "are hypersensitive to cocaine," she said. "They escalate their intake much more quickly, they're more impulsive. That cluster of traits goes along with risk for addiction."

Creed believes there could be a genetic problem that gives people too much or too little dopamine, setting them up for a higher risk of drug addiction.

"Cocaine is inducing a lot of its effects by inducing this pathological surge of dopamine," she said. "These genetic risk factors that give you too much or inappropriate dopamine all throughout development when your circuits are still forming, those are going to have persistent effects into adolescence and adulthood."