Neuroscientists shed new light on how heroin disrupts prefrontal brain function

A new study published in Neuropsychopharmacology sheds light on how heroin exposure alters brain function related to social interaction and drug craving. Researchers found that a specific group of brain cells in the prefrontal cortex responded less to social cues but more strongly to heroin-related signals after abstinence, a change that may contribute to relapse risk.

The study was motivated by the observation that people with opioid use disorder often struggle with maintaining stable social connections, and that social difficulties may increase the likelihood of relapse. Previous animal studies and clinical reports have suggested that opioid use not only disrupts reward systems in the brain but also impairs social behaviors. Since the prefrontal cortex is involved in both drug-seeking behavior and social cognition, the researchers wanted to explore how this region responds to social and drug-related cues after heroin use.

“People who are suffering from substance use disorders always values drug over any other rewards, such as social connection/interaction. We wanted to understand why this happens. How are drug users’ brains are different from healthy people?” explained study author Zi-Jun Wang, an assistant professor at the University of Kansas.

To do this, they conducted a series of experiments in mice using advanced imaging technology to observe real-time brain activity. The focus was on excitatory neurons in a subregion of the prefrontal cortex called the prelimbic cortex. These neurons are known to play a role in decision-making, impulse control, and processing of social information. The researchers used genetically modified mice that express a fluorescent indicator in these neurons, allowing them to monitor activity levels during specific behaviors.

The experimental procedure involved training mice to self-administer heroin by poking their noses into a designated port, which delivered a small dose of the drug. Control mice received saline instead. After 10 days of this self-administration phase, the researchers imposed a 14-day abstinence period. During and after this abstinence, the researchers tracked drug-seeking behavior, brain activity, and social interaction.

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The first finding confirmed that the mice trained to self-administer heroin displayed drug-seeking behavior after abstinence. When placed back into the testing chamber where they had previously received heroin, these mice made significantly more nose-poke attempts to trigger heroin-associated cues—even though no drug was delivered—than the control group. This demonstrated that the heroin-exposed mice retained a strong memory of the drug environment and remained motivated by drug-related signals.

In contrast, when these same heroin-abstinent mice were tested in a social setting, they spent significantly less time engaging with another mouse compared to control animals. This reduction in social behavior was observed in both male and female mice.

What made this study distinctive was the simultaneous measurement of neural activity during these behaviors. Using a method called fiber photometry, the researchers tracked calcium signals in the prelimbic cortex—signals that reflect neuronal activity. During the social interaction test, mice in the heroin group showed a lower level of activation in these excitatory neurons compared to the control group. But during the drug-seeking test, the same neurons showed heightened responses to heroin-associated cues.

“The prefrontal cortex is one of the key brain regions that malfunction after repeated drug exposure,” Wang told PsyPost. “This brain region gets over-activated by drug-associated cues/environments but get under-activated by social cues.”

The study also included recordings of baseline brain activity in the home cage, away from any stimuli. Mice in the heroin group showed reduced spontaneous activity in these neurons during resting conditions, suggesting that the overall functional state of the prefrontal cortex had shifted. These results imply that heroin exposure may leave the brain in a state where it is less responsive to social stimuli but more responsive to drug cues, even after a period of abstinence.

To probe the underlying causes of these changes, the researchers performed electrophysiological recordings of the same neurons. They found that synaptic inputs to these neurons—measured through specific types of electrical currents—were weaker in the heroin group. This suggests that long-term heroin exposure may reduce the strength of connections that normally keep these neurons active during rest and social exploration.

Interestingly, the researchers found a partial relationship between drug-seeking behavior and reduced social interaction in some mice. In particular, mice that made fewer drug-seeking attempts showed a stronger link between low social engagement and previous drug exposure. This may indicate that certain individuals are more vulnerable to the social consequences of drug use, which could in turn influence their risk of relapse.

The researchers also uncovered an unexpected correlation: mice with lower baseline neuronal activity in the prefrontal cortex tended to show stronger activation in response to heroin cues. While it’s unclear why lower resting activity would amplify responses to drug-related signals, the authors suggest it may involve compensatory mechanisms or changes in how inhibitory signals in the brain operate.

“We were surprised to see that although prefrontal activity is diminished at baseline and during social interaction, it is heightened in drug-related environments,” Wang said. “We were also surprised that this pattern in mice is similar to humans. Brain imaging studies focusing on cortical area show that people with substance abuse disorders have higher neuronal response to drug-associated cues, but lower response to other cues.”

Both male and female mice showed the same broad pattern of results, although some differences emerged. For example, the decline in brain activity during social interaction was slightly more pronounced in female mice, hinting at possible sex-specific vulnerabilities. Past studies have noted that female rodents may be more sensitive to social stress, which could interact with drug effects in ways that increase relapse risk.

While this research was conducted in mice, the authors believe the findings may help explain some of the social challenges faced by individuals recovering from opioid addiction. In particular, a brain that is less responsive to positive social cues might be less motivated to seek out healthy relationships, leaving individuals more susceptible to the lure of drug-associated environments.

The study does have limitations. One major question that remains is why the same brain region can show reduced responses to social cues while simultaneously showing increased responses to drug-related ones. The researchers plan to investigate the specific molecular pathways and neural circuits that drive this contrast in future studies. Understanding these mechanisms could help identify new targets for treatments aimed at restoring healthy social motivation and reducing the risk of relapse.

The researchers also note that the current imaging technique, while powerful, cannot distinguish among different groups of neurons within the prelimbic cortex. More refined imaging methods will be needed to tease apart how different cell populations contribute to the behaviors observed.

In the long term, the researchers aim to uncover how the brain’s reward system processes both social and drug-related stimuli after exposure to opioids. Their goal is to find ways to restore balanced activity in the prefrontal cortex, potentially reducing the motivation to seek drugs and improving social functioning in people recovering from addiction.

The study, “Prefrontal cortex excitatory neurons show distinct response to heroin-associated cue and social stimulus after prolonged heroin abstinence in mice,” was authored by Yunwanbin Wang, Junting Liu, Shuwen Yue, Lu Chen, Archana Singh, Tianshi Yu, Erin S. Calipari, and Zi-Jun Wang.