Resetting the Addicted Brain

A drug-induced similarity between the brains of rats and the brains of humans led National Institute on Drug Abuse (NIDA) researchers to a procedure that effectively wipes away compulsive cocaine addiction in rats—and they discovered a similar approach to curing human drug addiction along the way.

In a random study of rats, researchers created a rodent model that could mimic some of the key features of drug addiction, as well as incorporate a parallel for the negative consequences that come along with drug use. In the case of the rats, they were given, at random, a mild foot shock following cocaine training.

“The idea here is that something bad is going to happen as a consequence of lever pressing for that cocaine, but it is not momentarily tied to the moment that you press, because, that is also necessary in life,” said Dr. Antonello Bonci, NIDA scientific director and an author of the study. “You do something wrong, the negative outcome is not necessarily the next step, it could happen two hours later, or so on. That is why we used this model where, first of all, rats had to do work to get the cocaine. They had to push two levers in sequence, and then after training, we brought in this negative consequence of cocaine taking.”

As a result of the foot shock, 70 percent of rats gave up taking cocaine, Bonci revealed. The other 30 percent, which became the focus group for the study, were still cocaine-seeking regardless of the shock. “This 30 percent of rats were the ones we called ‘compulsive cocaine seekers,’” he said.

Now able to examine the brains of rodents identified “compulsive,” researchers found that an important area of these brains, the prelimbic cortex, was silent as a consequence of cocaine exposure and compulsive cocaine use.

Despite this hypoactivity, the rodents’ prelimbic cortex was still responsive to optogenetics, and researchers, using light-sensitive proteins and laser wavelengths, stimulated the silent brain region in “a pacemaker-like fashion,” Bonci said.

“In rodents you can show causality, a connection between cause and effect, so we took advantage of optogenetics. To show causality we needed to show that if we restored activity in this silent brain region—if it meant anything for the rat—then this cocaine craving and seeking would be gone, and that’s exactly what we observed,” he said. “Despite weeks and weeks and weeks of extensive cocaine access, and despite these rats being exposed to four days where this shock was given after taking cocaine, when we turned on the silent prefrontal cortical region with this very low frequency stimulation, the craving and the interest to take cocaine vanished immediately.”

The human connection

The “amazing connection,” Bonci said, was that the silent prelimbic cortex in rodents has a human brain equivalent, the anterior cingulate cortex, which studies have shown to be hypoactive after human cocaine exposure as well.

“In humans, what we can do to stimulate this quiet brain region is to use transcranial magnetic stimulation (TMS),” Bonci said. TMS, a technique that uses electromagnetic induction to non-invasively affect neuron polarization, has been used to treat a variety of neurological and psychiatric ailments.

“That’s why we’re so excited. We don’t have to wait for a new molecule to be designed, tested and then eventually 10 to 15 years from now be used in humans,” Bonci said. “We can use a very well-accepted, non-invasive stimulation technique, to try and create a certain pacemaker-like activity to reactivate these hypoactive frontal portions of the brain, to try to basically mirror what we observed in rodent models.”

Defining human treatment

Although Bonci said human clinical trials were being developed “as we speak,” there are still many questions and concerns researchers must answer before using TMS to treat compulsive cocaine addiction, or any other type of drug addiction, in humans.

“There is a very quick temper of translation here, from discovery to being able to try to act on people with this cocaine taking problem,” he said, “but there are many questions that we haven’t answered yet. For example, how many sessions do we need in order to create a long-lasting effect? What is going to be the frequency, or what will be too much? We have a lot of serious conversations going, to define how to stimulate the human brain with this technique.”

As those conversations progress, Bonci is hopeful that the team will be able to begin patient recruitment by the end of this year or early 2014 in order to help treat the growing drug addiction problem.

“There is a very optimistic message here also, that while it is true this brain was changed as a consequence of cocaine exposure, it also retains a lot of flexibility and you can actually remodel a behavior that is negative,” Bonci said. “We know that once the stimulation is on, at least for that period of time, the rats’ interest in pressing for cocaine is gone, but beyond that, we don’t know…Do we need one or ten sessions to make sure that the rebuilding of a new memory, one which is not focused on lever-pressing for cocaine, is going to last? These are questions that we will be answering hopefully in the near future.”

The study, “Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking,” was recently published in Nature. Lead author of the study was Dr. Billy Chen, also of NIDA. Additional research was conducted by Intramural Research Program of NIDA, part of the National Institutes of Health, and the University of California, San Francisco.