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Studying addiction at the cellular level to find treatment for binge behavior

Jocelyn M. Richard, a postdoctoral fellow in the Johns Hopkins University Department of Psychological and Brain Sciences, holds a cord that is inserted into a rat's brain so  researchers can monitor neurons within the rat's brain.

The aroma of wine or beer. A glimpse of white powder. The sound of music wafting from a neighborhood ice-cream truck.

Scientists have long known that such environmental cues can spark cravings — and trigger relapses — for those who struggle with addiction.


What happens in the brain as these processes occur is less well understood. But a group of neuroscientists based at the Johns Hopkins University has shed new light on the question, stirring hopes that researchers might one day develop interventions that blunt the urge to binge.

The Hopkins team led by Jocelyn Richard, a postdoctoral fellow in psychological and brain sciences at Hopkins, and Patricia Janak, a professor in the same department, found in a study last year that neurons within a small, little-studied structure in the lower brain — the ventral pallidum — respond far more robustly than expected in the presence of such cues.


Further, those neurons, once excited, triggered binge-like actions so consistently that researchers could predict the behaviors.

The findings suggest that neurochemical activity in this nut-size region plays a key role in motivating addictive individuals to indulge when the cues are present — and that science might one day be able to tamp down the urges by neurochemical or other means.

The team explored the subject by training rats to realize that when they heard certain sound cues — a siren or a series of quick beeps — and pushed a lever, they would get a drink of sugar water.

The researchers monitored neural activity within the rats' ventral pallida as they carried out the tasks, then observed the animals' behavior.

The more activity in that portion of the brain, as it turned out, the more quickly and eagerly the rats went after their treats.

The findings appear in an article in the June 15 issue of Neuron, a neurosciences journal.

"Our study may present more questions than it does answers, but we found ourselves getting closer to the part of the brain that is responsible for driving this kind of behavior, and that's exciting," said Richard, the lead author of the study.

Science's understanding of the brain is still at a "pretty rudimentary stage," Richard said, and that includes the circuits that control motivation, reward and pleasure, functions strongly associated with the neurobiology of addiction.


Most researchers are familiar with the so-called dorsal basal ganglia, a tightly clustered network of neural structures buried in the cerebrum (the principal mass of the brain). These ganglia, or networks of nerve cells, are thought to be involved in the regulation of behavior and emotions, and in helping to select and trigger voluntary movements.

Fewer are familiar with a similar network deeper in the brain — the ventral (lower) basal ganglia, a smaller network more specifically associated with addiction, reward-seeking behavior and the experience of pleasure.

Within that network lies an array of interconnected substructures that govern and channel those functions.

Two of the more important are the nucleus accumbens, an aggregate of neurons scientists have long believed to be stimulated early in the process, and the ventral pallidum, a smaller, less widely studied structure believed to serve a secondary function later.

Though neuroscientists knew the two to be involved in regulating pleasure and reward, few had subjected their relationship to rigorous testing. Richard's team chose to change that.

In the first part of their study, the researchers exposed the rats to the sound cues, monitoring the neural activity in their nucleus accumbens and ventral pallidum areas simultaneously.


What they found surprised them: Only 20 percent of the neurons in the nucleus accumbens reacted, but an astounding 70 percent in the supposedly less important ventral pallidum did.

That is more than three times the number usually associated with a robust response — and strongly suggests that the ventral pallidum might be an underappreciated powerhouse in the pleasure-seeking system.

One expert in the field called the finding a game-changer.

"A great deal of work has focused on brain structures upstream of the ventral pallidum — like the nucleus accumbens — as a target for potential addiction treatments," said Kate Wassum, a behavioral neuroscientist at the Integrative Center for Addictive Disorders at the University of California-Los Angeles. "This study suggests we should put more focus on the ventral pallidum itself."

But the study had two more stages. Both produced interesting results.

First, the group wanted to know what effect, if any, this elevated activity within the ventral pallidum might have on the rats' behavior. Would it, for example, make them more likely to press the lever that delivers treats? Would the animals do it more quickly or more intensely?


As it turned out, the higher the neural activity grew, the more frequently — and the more rapidly — the rats attacked the lever. The correlation was so strong that the team could use neural-activity levels to predict how often and how quickly the animals would go for their treats.

Even though the cues in the study dealt with food, Wassum said it is reasonable to conclude that the findings would be the same for most addictive substances, since all are believed to "hijack" the brain's normal motivation circuits in similar ways.

It was like learning what level of excitement in the ventral pallidum might cause addiction-prone humans to reach for an alcoholic drink, indulge in drug abuse or down a soda or a Big Mac when exposed to their own triggering cues.

Richard said the findings create an opening to explore how, why and under what conditions individuals battling addiction make that decision to binge, often in spite of their better judgment.

"Taken together, these things suggest that these neurons — the way they respond to cues — are driving something bigger, matters such as motivation and reward," Richard said.

In their final stage, the researchers addressed another question: If they were to calm neural activity in the ventral pallidum, would that reduce the rats' treat-seeking behavior?


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They used a new, targeted-light technology called optogenetics to suppress that activity — and the rats pulled the levers more slowly and less frequently.

This ability to calm the reaction to cues or triggers could one day prove crucial for those who are trying to curb addictive behaviors, Richard said.

Richard began the inquiry in 2013, when she was a postdoctoral fellow at the University of California-San Francisco, and continued to spearhead it when she moved to Baltimore — and Janak's lab in the psychological and brain sciences department, a division of the Krieger School of Arts and Sciences at Hopkins — two years later.

Howard L. Fields, director of the Wheeler Center for the Neurobiology of Addiction at UCSF, and Frederic Ambroggi, a researcher at Aix-Marseille University in France, joined Janak as co-authors of the study, which was supported by grants from the National Institutes of Health and the state of California.

To Richard, the findings only pose more questions — and open up more lines of inquiry — for researchers in the still-mysterious neuroscience of addictive behavior.

"We're still figuring out the best ways to study the brain," she said.