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Mini-Brains and More Provide New Insights on Addiction and Depression

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From left, Wilson Compton, Wayne C. Drevets, and Thomas Hartung discuss the neuroscience of addition at a 2016 AAAS Annual Meeting press briefing. | Ashley Gilliland

A ball of brain cells the size of a fly’s eye and a 1990s club drug are just some of the more unusual test subjects being used by scientists as they look for ways to break the grip of addiction and mood disorders that affect millions worldwide.

The research has taken on a new urgency as levels of U.S. opioid addiction have risen in the past fifteen years. Opioid drugs include prescription painkillers such as Vicodin or OxyContin and illegal drugs like heroin. According to the Centers for Disease Control and Prevention, there was a fivefold increase in the U.S. heroin death rate between 2002 and 2014, with 10,574 heroin overdose deaths counted in 2014.

At a news briefing Friday at the 2016 AAAS Annual Meeting, National Institute on Drug Abuse Deputy Director Wilson Compton said the rise in opioid addiction was due in part to a “tremendous availability of prescriptions” for opioid medications, along with easier access to heroin.

“So we have a large population at risk because of the environmental availability of prescription opioids, and then a portion of them make this transition [to illegal opioids] because their friends or their drug-using colleagues show them this access to heroin,” Compton said. “Once they’ve made that transition they find out that it’s cheap and available, in many parts of our country.”

Scientists need new ways to test exactly how drugs like opioids—and new potentially addictive substances such as e-cigarette additives—are affecting the brain, and how these addictions might be treated best, the briefing speakers said.

Enter the mini-brain, a ball of interacting brain cells just visible to the human eye. The brain balls contain networked neurons and many of their surrounding support cells. One hundred of them can grow together in a lab dish. They are created by reprogramming a person’s adult skin cells to become stem cells capable of growing into any specialized type of cell, and then reprogrammed again to become brain cells. The process, called iPSC, won its discoverers the 2012 Nobel Prize in Physiology or Medicine.

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A depiction of a mini-brain. | Johns Hopkins University

Thomas Hartung, the director of the Center for Alternatives to Animal Testing at Johns Hopkins University’s Bloomburg School of Public Health, runs one of five labs in the world that grow the mini-brains for research, and he hopes they will eventually do away with the need for testing medications or toxins on animals.

"While rodent models have been useful, we are not 150-pound rats,” said Hartung. “And even though we are not balls of cells either, you can often get much better information from these balls of cells than from rodents.”

For decades, scientists have been studying brain cells in two-dimensional configurations, like “eggs frying in a pan, sunny-side up,” said Hartung. The three-dimensional mini-brains are better brain models, he added, because they recreate the same kinds of cell-to-cell contacts and interactions that occur in a full-size human brain.

Hartung’s lab at Johns Hopkins is developing standardized sets of mini-brains that can be used to test different drugs and toxins. But he said mini-brains also could be built from the skin cells of people with autism, or Parkinson’s disease, to get a closer look at what kinds of genetic and environmental factors combine to create these complex diseases. In the future, he suggested, these mini-brains may even be used routinely in personalized medicine, to test how effective a particular medicine might be for a patient before giving him a dose.

The latest research on full-sized human brains shows that addiction and mood disorders such as depression share circuitry and chemistry in the brain, and that depression could even be called “the first cousin of addictive disorders,” said Wayne Drevets, vice president and disease area leader in mood disorders at Janssen Research & Development, a Johnson & Johnson pharmaceutical company.

It was this close connection that helped researchers understand a surprising 2006 report that the anesthetic ketamine, which saw a resurgence of popularity in the 1990s as a recreational drug used in dance clubs, could be a powerful antidepressant.

Drevets and his company are testing a type of the drug called esketamine, to see if it can be delivered in a nasal spray to treat people whose depression symptoms have not been alleviated by any other medications.

“We learned because of this overlapping circuitry for drugs of abuse and mood disorders,” Drevets said, that a single dose of esketamine could reshape a person’s brain circuits in a way that relieved their depression symptoms persistently for several days. The nasal form of the drug may be available by 2018, he said.