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July 02, 2014

Dr. Antonello Bonci, Scientific Director of NIDA’s Intramural Research Program (IRP), talks about switching off animals’ compulsive cocaine seeking by optogenetically activating the prefrontal cortex, and the implications of this work for people. His comments supplement a NIDA Notes article and a video discussion of his and his colleagues’ experiments.

NIDA Notes: What did your study show?

Photo of Dr. Antonello BonciIn this podcast, Dr. Antonello Bonci walks viewers through experiments that showed that prefrontal cortex activity levels may constitute a simple switch controlling whether or not animals compulsively seek cocaine. He discusses how these findings by NIDA’s IRP may translate to treatments for people with cocaine addiction.

Dr. Bonci: We found that we could turn rats into compulsive cocaine seekers by shutting down activity in the prefrontal cortex (PFC) and make them quit seeking cocaine by reactivating the PFC. This suggests that there is a switch-point in the PFC that determines or strongly influences whether an animal will persistently seek cocaine.

The same may hold for people. We already know that people who are addicted to cocaine have very low activity in the PFC—in fact, that was a starting point for our study.

In the hope that our findings will translate to people, we will soon begin a trial to test whether PFC stimulation can help patients with cocaine addiction reduce their drug use. In the trial, we will stimulate the brain noninvasively with magnets, rather than with the invasive optogenetics technique we used in our animal study.

NN: Why should PFC activity make such a difference?

Dr. Bonci: People whose PFC is normal can foresee the consequences of their actions and avoid doing things that will cause them trouble down the line. People whose PFC is hypoactive have reduced ability to do this. They are often unable to switch from a counterproductive behavior to another, more beneficial, one. They get stuck in repetitive, compulsive behaviors, such as using drugs.

We hypothesize that shutting down rats’ PFC in our study caused a similar effect: It rendered the animals unable to link their experience of cocaine to that of the unpleasant foot shocks that accompanied the drug. Conversely, when we stimulated rats’ PFC, it restored this ability, and they stopped seeking the drug.

The PFC is not the only such “switch” in the brain. For example, some patients who had strokes that damaged the region called the insula quit smoking immediately. Their urge to smoke left them completely.

Having said that, there is a mystery that remains to be solved. We know that addictive drugs change many, many brain regions, as many as 90 or more, and these regions are organized into overlapping circuits. We have no idea how, given this enormous complexity, just shutting down or tuning up one single region can produce such profound effects.

NN: Might these findings also apply to other drugs?

Dr. Bonci: Maybe. The PFC is extremely important in making decisions based on evaluating the likely outcomes of an action. Therefore, its strength or weakness might well be a determinative factor with respect to compulsive use of every major drug of abuse. Alternatively, we might discover that drugs other than cocaine, through their different pharmacological mechanisms of action, produce compulsive effects via different brain regions and systems.

NN: Why was the optogenetic technology essential for achieving your results?

Dr. Bonci: Optogenetics is an amazing new tool that every field of science is using right now. It enables researchers to truly mimic natural brain activity. The laser beams are so precise that we were able to deliver pinpoint stimulation or inhibition to the prelimbic region of the PFC. The beams are very fast, so we were able to stimulate and inhibit cells at the same millisecond speeds that cells use to communicate with each other.

Of note, we didn’t apply a very high frequency of stimulation in our experiment. We used what a pacemaker in a heart would do. One hertz, or one stimulation, per second, was enough to reactivate PFC cells that had been shut down by cocaine exposure and wipe out compulsive cocaine seeking. This tells us that we won’t need to apply massive amounts of magnetic stimulation with patients in our clinical trial.