Silencing Infralimbic Cortex Neurons Suppresses Cocaine Craving

The infralimbic cortex, a region of the brain that controls addictive behavior, can be reprogrammed to ease lab rats’ cocaine urges, research from University of Iowa has found. The finding could help users kick the habit with the help of drugs that target the infralimbic cortex – or with improved behavioral treatment for substance addiction and relapse.

Corresponding author Andrea Gutman, postdoctoral researcher in the UI Department of Psychological and Brain Sciences, along with colleagues performed a series of experiments in which rats were given cocaine, then taken off the drug.

The infralimbic cortex, a part of the prefrontal cortex located toward the front of the head, is responsible for forming habits and regulating behavior. Think of it as a mental green light or a check on destructive or embarrassing tendencies.

Researchers already knew about the role, but they were unsure how it controlled cravings and other habit-forming behaviors – or whether the infralimbic cortex could be manipulated to temper impulses. The UI team worked with a group of rats that were administered cocaine when they pressed a lever with their paws; the rats did so for two hours per day over the course of two weeks.

Curb Your Enthusiasm

Over the next two weeks, the rats received no cocaine when they pressed the lever. When they realized they were no longer getting the drug, the rats pressed the lever less frequently, until, by the end of the two-week period, “they hardly pressed the lever at all,” Gutman says.

In other words, at least some of the rats learned to curb their addiction.

A second group of rats followed the same regimen as the control group and were allowed to use cocaine for two weeks. However, in this second group, the researchers used optogenetics to turn off pyramidal neurons in the rats’ infralimbic cortex just as the animals pressed the drug-dispensing lever.

By silencing those neurons for a period of 20 seconds every time the rats pressed the lever, the researchers in effect prevented the rats from learning to curb their drug appetite. The rats’ cravings remained as intense as in the beginning of the experiment, even though they weren’t receiving the drug.

“They’re failing to learn to inhibit their cocaine craving. They want the cocaine just as much,”

says Gutman, who works in the lab of Ryan LaLumiere, assistant professor in the UI Department of Psychological and Brain Sciences.

Infralimbic Cortex Function

The researchers silenced the neurons in the rats’ brains for the first five days of the cocaine-less two-week period. They found that these five days had a major impact on how effectively rats learned and began to adapt to the drug’s absence. The rats whose neurons were silenced were more likely to relapse than those that underwent withdrawal, the study found.

The results strengthen the hypothesis that the infralimbic cortex plays an important role in the suppression of addictive behavior. It also points to when the region could best be “taught” to curb a habit.

“No study has looked intensively at exactly how the infralimbic cortex functions, nor the importance of the first five days of treatment when it comes to curtailing drug-seeking behavior,” says LaLumiere, the paper’s co-author. “And while our experiments involved cocaine, we think the results could hold true for the infralimbic cortex’s role in conditioning withdrawal and relapse from other addictive substances, including opioids.”

The work was funded by the National Institute on Drug Abuse (a branch of the National Institutes of Health), the Department of Veterans Affairs, and the Brain & Behavior Research Foundation.

Andrea L. Gutman, Kelle E. Nett, Caitlin V. Cosme, Wensday R. Worth, Subhash C. Gupta, John A. Wemmie, Ryan T. LaLumiere
Extinction of Cocaine Seeking Requires a Window of Infralimbic Pyramidal Neuron Activity after Unreinforced Lever Presses
The Journal of Neuroscience, 2017; 37 (25): 6075 DOI: 10.1523/JNEUROSCI.3821-16.2017

Image: walknboston/Flickr

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