AsianScientist (Apr. 27, 2026)–Drug addiction has a high chance of relapse. Some people may start using drugs again even after decades of abstinence. The reasons for relapse were not fully understood, but stressful life events and reminders from the past have been identified as triggers. These stressors and cues bring back memories of feeling good while using drugs and create a strong desire to use again. Previously, this phenomenon was attributed to a decline in prefrontal cortex (PFC) function, which regulates impulses. However, researchers have recently found that addiction relapse is not caused by a simple decline in brain function, but by an imbalance in specific neural circuits.
A joint research team from the Department of Brain and Cognitive Sciences, Korea Advanced Institute of Science and Technology (KAIST) and the University of California, San Diego (UCSD) identified how specific inhibitory neurons in the prefrontal cortex regulate cocaine-seeking behaviour. Their findings were published in the journal Neuron.
For the study, scientists trained mice to self-administer cocaine by pressing a lever, creating addiction-like behaviour similar to human drug dependence.
After this training period, cocaine was removed, and the mice went through abstinence so researchers could study relapse-like behaviour.
The scientists focused on specialised inhibitory brain cells, particularly parvalbumin-positive (PV) interneurons, which regulate the activity of nearby neurons, as well as projection neurons in the medial prefrontal cortex (mPFC) that send signals to reward-related brain regions.
Using brain activity recording, optogenetics (switching cells on and off using light), circuit tracing, and synapse analysis, they examined how cocaine exposure changed communication between these cells.
The results showed that different inhibitory neurons played different roles during cocaine seeking, but PV interneurons showed the most significant changes after cocaine exposure.
These PV cells, which make up about 60–70% of inhibitory neurons in the PFC, act like a “brake gate” by controlling excitatory signals and helping suppress impulses when brain activity remains balanced.
The researchers found that PV cells became highly active when mice attempted to seek cocaine. However, during “extinction training,” where mice were trained to stop seeking the drug, the activity of these cells significantly decreased. This showed that the activity of PV cells is not permanently fixed by addiction and can be readjusted.
The team also confirmed that artificially suppressing PV cell activity significantly reduced cocaine-seeking behaviour in mice, while activating these cells caused drug-seeking behaviour to continue even after extinction training. This effect was specific to drug addiction and did not appear with general rewards like sugar water.
It was also not seen in somatostatin (SOM) cells, another type of inhibitory neuron, showing that PV cells selectively regulate addiction-related behaviour.
The researchers further identified the specific brain circuit involved. Signals from the prefrontal cortex were transmitted to the Ventral Tegmental Area (VTA), a key reward-related brain region. This pathway acted as the main channel regulating whether the mice would seek cocaine again.
PV neurons functioned as a “regulatory switch,” controlling signal flow to influence dopamine signalling and either maintain or suppress addictive behaviour.
“This research shows that drug addiction is a circuit-level problem arising from a collapse in the regulatory balance of specific neurons and downstream neural circuits. The discovery that parvalbumin (PV) cells act as a ‘gate’ for addictive behaviour will provide a crucial lead for developing precision-targeted treatment strategies in the future,” said Se-Bum Paik, associate professor, Department of Brain and Cognitive Sciences at KAIST.
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Source: Korea Advanced Institute of Science and Technology (KAIST); Image: The Yuri Arcurs Collection/reepik
This article can be found at: Distinct interneuronal dynamics selectively gate target-specific cortical projections in drug seeking
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