Summary: Silencing pyramidal neurons in the infralimbic cortex made rats more likely to relapse than rats that underwent normal withdrawal from cocaine. These results support growing evidence that the infralimbic cortex plays a critical role in suppressing addictive behavior and encoding extinction learning.
Source: University of Iowa
The brain can adapt, reorganize, and learn new patterns of behavior. Could it also be taught to suppress powerful drug cravings? Researchers at the University of Iowa studied how activity in the infralimbic cortex—a region of the prefrontal cortex involved in habit formation and behavioral control—affects cocaine-seeking and relapse. Using a closed-loop optogenetic approach in rats, the team identified a precise time window after an unrewarded response when infralimbic pyramidal neuron activity is necessary for extinction learning and for reducing later drug-seeking behavior.
In the experiments, male Sprague Dawley rats self-administered cocaine by pressing a lever for two hours a day over two weeks. After this self-administration period, animals entered an extinction phase lasting two weeks during which lever presses no longer delivered cocaine. Under normal conditions, rats gradually reduced lever pressing across extinction sessions until they rarely pressed the lever, indicating learning that the lever no longer provided the drug.
To test the role of infralimbic cortex (IL) activity in that learning process, researchers used optogenetics to temporarily silence IL pyramidal neurons for 20 seconds following each unreinforced lever press. This inhibition was precisely timed and contingent on the animal’s response. When IL neurons were silenced in that post-press window during the first five days of extinction, rats failed to reduce lever pressing within sessions and showed stronger cocaine-seeking during later cued reinstatement tests, even though the extinction sessions that followed had no neural inhibition. In other words, preventing IL activity immediately after an unrewarded response impaired the normal extinction process and increased vulnerability to relapse.
Control experiments confirmed the specificity of this effect. Noncontingent (pseudorandom) inhibition of the IL during extinction did not produce the same impairment, illumination alone without opsin expression had no effect, and parallel food-seeking tests did not replicate the pattern seen with cocaine. Inhibition of the prelimbic cortex (a different prefrontal region) immediately after lever presses produced different results: it decreased lever pressing during shortened extinction sessions but did not influence subsequent reinstatement. Together, these findings indicate that IL activity specifically during the immediate post-response period encodes new information about the changed contingency—namely, that a lever press no longer results in cocaine—and that this encoding is important for long-term extinction and relapse prevention.
Lead author Andrea Gutman, a postdoctoral researcher in the UI Department of Psychological and Brain Sciences, notes that these results reveal both a functional role for the infralimbic cortex in suppressing drug-seeking and a critical timing for when that region must be active to support extinction. Co-author Ryan LaLumiere emphasizes that the first several days of treatment or abstinence may be especially important: silencing IL neurons just during that early window had lasting consequences on relapse susceptibility.
Because the study used cocaine as the drug of abuse, the authors suggest the mechanism may extend to other substances, including opioids, although further work is needed to confirm generality across drugs and across species. The findings point to potential therapeutic strategies that could strengthen or mimic infralimbic cortex activity at key moments during behavioral treatment, or to pharmacological approaches that target the neural processes underlying extinction learning to reduce relapse risk.
Contributing authors include Kelle Nett, Caitlin Cosme, Wensday Worth, Subhash Gupta, and John Wemmie, all affiliated with the University of Iowa. Funding for the research was provided by the National Institute on Drug Abuse (NIH), the Department of Veterans Affairs, and the Brain & Behavior Research Foundation. The findings were published in the Journal of Neuroscience in 2017 under the title “Extinction of Cocaine Seeking Requires a Window of Infralimbic Pyramidal Neuron Activity after Unreinforced Lever Presses.” DOI: 10.1523/JNEUROSCI.3821-16.2017.
- The infralimbic cortex is essential for encoding extinction learning after an unrewarded drug-seeking response.
- A brief, immediate post-response window of IL activity is necessary for rats to suppress cocaine-seeking and reduce later relapse.
- Disrupting IL activity during that window impairs within-session extinction and enhances cued reinstatement of drug-seeking.
- These results point to precise timing as a target for interventions—behavioral or pharmacological—that aim to strengthen extinction and prevent relapse.
Abstract (condensed)
The infralimbic cortex mediates extinction learning and active suppression of cocaine-seeking. Using activity-guided optogenetics in rats, investigators transiently inhibited IL pyramidal neurons for 20 seconds immediately after unreinforced lever presses during early extinction. This post-press inhibition increased active lever pressing during extinction and produced greater cocaine-seeking during later cued reinstatement, effects not observed with noncontingent inhibition, illumination controls, or food-seeking controls. Inhibition of prelimbic cortex produced different, limited effects. These results indicate that IL activity immediately after an unrewarded instrumental response is necessary for normal extinction of cocaine seeking and for reducing subsequent relapse risk.