Vulnerability to cocaine uncovered in adolescent mouse brains

Editor’s note: Guest post from Neuroscience graduate student Brendan O’Flaherty. Companion paper to the Gourley lab’s recently published work on fasudil, habit modification and neuronal pruning.

An Emory study has discovered why teenager’s brains may be especially vulnerable to cocaine. Exposure to small amounts of cocaine in adolescence can disrupt brain development and impair the brain’s ability to change its own habits, the study suggests.

Guest post from Brendan O’Flaherty

The results were published in the April 1, 2017 issue of Biological Psychiatry, by researchers at Yerkes National Primate Research Center.

Drug seeking habits play a major role in drug addiction, says senior author Shannon Gourley, PhD, assistant professor of pediatrics, psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center. The first author of the paper is former Emory graduate student Lauren DePoy, PhD.

When it comes to habits, cocaine is especially sneaky. Bad habits like drug use are already very difficult to change, but cocaine physically changes the brain, potentially weakening its ability to “override” bad habits. Although adults are susceptible to cocaine’s effects on habits, adolescent brains are especially vulnerable.

“Generally speaking, the younger you are exposed to cocaine in life, the more likely you are to have impaired decision making,” Gourley says.

Shannon Gourley, PhD, in lab

To understand why adolescent brains are especially vulnerable to cocaine, the researchers studied the effects of cocaine exposure on how the mice make decisions about food.

“I think it’s pretty amazing that we can actually talk to mice in a way that allows them to talk back,” Gourley says. “And then we can utilize a pretty tremendous biological toolkit to understand how the brain works.”

Researchers injected adolescent mice five times with either saline or cocaine. Both groups of animals then grew up without access to cocaine. Researchers then trained the mice to press two buttons, both of which caused food to drop into the cage. Since both buttons rewarded the mice equally, the mice pushed each button half the time.

Over time, pushing the two buttons equally could become a habit. To test this, the researchers then played a trick on the mice. When one of the buttons was exposed, the researchers starting giving the mice food pellets for free, instead of rewarding them for button-pressing.

“What the mouse should be learning is: ‘Ah hah, wait a minute, when I have access to this button I shouldn’t respond, because my responding doesn’t get me anything,‘” Gourley says.

Finally, the mice were released back into the chamber and given a choice between both buttons. They had two choices: they could pursue the goal of maximizing their food by mostly pressing the lever that still rewards them. Or, they could fall back on their old habits and press each button 50% of the time, even though one button didn’t reward them anymore. The researchers call these choices “goal-directed behavior” and “habitual behavior” respectively.

During adolescence, both saline-injected and cocaine-injected mice used the more efficient “goal-directed” strategy. However once the mice grew up, the effects of early-life cocaine became obvious: the saline injected mice still used “goal-directed behavior”, but the cocaine-injected mice used the inefficient “habitual behavior” strategy.

With more training, the cocaine-injected mice could eventually catch up and learn the “goal directed” behavior, but they had a harder time setting goals and learning new strategies than normal mice. In the meantime, they defaulted to their old, inefficient habits.

It takes about nine times less cocaine to cause habitual behavior in adolescent mice than in adult mice. “The reason that adolescents are so vulnerable [to cocaine] is that the adolescent brain is still developing,” Gourley says. “It’s pretty stunning to me that in this very low dose and very brief period of cocaine exposure has these long, long term effects [in mice]”.

To investigate why adolescent mice were so vulnerable to cocaine, the researchers looked at a brain region called the orbitofrontal cortex. The orbitofrontal cortex is critical for impulse control and planning in both mice and humans. Because the orbitofrontal cortex is still maturing in adolescence, it could be especially vulnerable to cocaine during this delicate process.

The researchers again injected adolescent animals with cocaine or saline, and then let the mice grow up. They then looked at neurons in the orbitofrontal cortex, and counted their connections with other neurons, called synapses. Because synapses allow neurons to communicate, altering the number of synapses could massively affect how well the orbitofrontal cortex works. Indeed, orbitofrontal neurons from cocaine-exposed mice had fewer synapses than neurons from typical mice.

Cocaine appears to eliminate synapses by hijacking a normal process called “synaptic pruning”. During adolescence, orbitofrontal cortex neurons naturally eliminate (“prune”) unnecessary synapses, but keep important ones. Cocaine derails this process, causing neurons to eliminate too many synapses, including important ones. These effects could be permanent.

However, the researchers could reverse the effects of previous cocaine exposure by giving an experimental drug to adult mice. The drug ifenprodil helps stabilize orbitofrontal synapses. Mice exposed to cocaine and ifenprodil had more synapses in the orbitofrontal cortex than mice exposed to cocaine alone. Ifenprodil also allowed the mice to engage in goal-directed behavior in the button-pressing task, countering the effects of cocaine exposure.

Ultimately, ifenprodil and similar drugs could be used in combination with other therapies to better rehabilitate cocaine addicts. “One direction I think could be fruitful for addiction research is to pair [drug] therapies with cognitive behavioral therapies, which would help addicts develop goals, [and] develop strategies to achieve those goals” Gourley says.

This work was supported by Children’s Healthcare of Atlanta, the Emory Egleston Children’s Research Center, the National Institutes of Health (Grant Nos. DA015040 and DA034808) and the Office of Research Infrastructure Programs (P51OD011132, primate centers).

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Quinn Eastman

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