Recent evidence suggests that a single dose of the psychedelic compound psilocybin reduces reward-seeking, providing evidence that it has the potential to treat substance use disorders. New research published in European Journal of Neuroscience revealed that this decrease in motivation is associated with increased activity in specific inhibitory brain cells surrounded by a protective net. These findings help explain how psychedelics cause long-lasting changes in the brain circuits that govern decision-making and addiction.
Substance use disorders include a pattern of increased drug intake and difficulty resisting urges. The main feature of these symptoms is impulsiveness of choice. This psychological concept explains the tendency to overestimate small immediate rewards over larger rewards that require waiting. People and animals with high choice impulsivity are more likely to suffer from addiction and have a higher risk of relapse.
The dorsomedial prefrontal cortex is a region of the brain that plays a major role in processing reward cues and controlling decisions based on the value of those rewards. This brain region is highly enriched with specific serotonin receptors. These receptors serve as the main cellular targets for classic psychedelic drugs like psilocybin. When someone ingests psilocybin, the compound binds to these receptors and produces a variety of effects.
Within this brain region are fast-firing cells called parvalbumin interneurons. These cells act as inhibitors, meaning they calm down or suppress the activity of other brain circuits. Many of these inhibitory cells are wrapped in specialized structures called perineuronal nets. These microscopic meshes are part of the extracellular matrix, a web of proteins and sugars that provides structural support and controls how brain cells adapt and change over time.
Previous clinical trials have shown that a single session of psilocybin-assisted therapy can help reduce alcohol and nicotine consumption in humans. Animal models have also shown a reduced risk of relapse after a single dose of the compound. However, the precise biological mechanisms behind these persistent behavioral changes remain relatively unknown.
Alberto del Arco, associate professor and director of the Neurophysiology and Behavioral Laboratory at the University of Mississippi’s College of Applied Sciences, wanted to understand these long-term effects. “Recent research in animal models and clinical trials suggests that psilocybin may be an effective treatment for substance use disorders,” Del Arco said. “However, there are critical gaps in our knowledge about how this psychedelic drug alters reward-seeking behavior.”
To investigate this process, the authors used adult male Long-Evans rats. The researchers put the animals on a mild diet a few days before training began to ensure they were motivated to participate. “To address this gap, we trained rats in a reward-seeking task in which they made a decision to choose (i.e., press a lever) between a small reward now (one sugar pellet after 1 second) and a large reward later (three sugar pellets after 10 or 20 seconds),” Del Arco explained.
This delay discounting task was performed in a soundproof room equipped with two retractable levers and a food dispenser. Daily sessions included forced-choice trials in which only one lever was activated to ensure that rats were paying attention to the rules and experiencing a time delay. The session also included free-choice trials, in which both levers were activated. This setup allowed the researchers to observe the rats’ natural preferences as latency increased.
Training continued for approximately 12 days until the animals exhibited stable and predictable decision-making patterns. Once the rats mastered this task, the scientists divided them into two groups. Six rats received a single intraperitoneal injection of psilocybin at a dose of 1 milligram per kilogram of body weight, and the remaining eight rats received a simple saline injection as a control group.
After the injection, the researchers placed the rats in a transparent box and recorded their behavior for 60 minutes. They counted the number of head twitches each rat exhibited. This is a standard behavioral marker in rodents and indicates that the psychedelic drug activated serotonin receptors in the target’s brain. As expected, rats given psilocybin had a significant increase in head twitching compared to the control group.
“We then gave the rats a single intraperitoneal (or vehicle) injection of 1 mg/kg psilocybin and tested the animals in this task 24 and 48 hours after the injection,” del Arco told PsyPost. When the animals were examined several days later, the drug was completely cleared from the animals’ systems. At 24 hours, the psilocybin and saline groups showed similar performance.
However, the results changed at 48 hours. “The long-term effects 48 hours after psilocybin administration were somehow surprising,” Del Arco noted. “We found that psilocybin was effective 48 hours after injection, reducing the number of times the animals chose the higher reward.”
Rats given psilocybin had a markedly reduced preference for high-value rewards and took significantly longer to press the lever to obtain high-value rewards compared to the control group. This decrease in preference was not dependent on the length of the waiting period, so the behavior did not reflect changes in impulsivity. In general, the rats seemed less motivated to pursue large rewards. They also maintained accuracy during forced-choice testing. This suggests that the drug did not impair their attention or basic motor skills.
After final behavioral testing, the researchers euthanized the animals and extracted their brains for microscopic analysis. They used a special chemical marker to highlight inhibitory parvalbumin cells, surrounding perineuronal nets, and a specific protein called c-Fos that indicates recent cellular activity. “We also analyzed the brains of these animals 48 hours after psilocybin administration and found activation of a type of cortical inhibitory neuron (parvalbumin) and changes in the extracellular matrix (a structural element involved in brain plasticity),” Professor Del Arco explained.
In the deep layers of the prefrontal cortex, rats treated with psilocybin had a higher density of active inhibitory cells wrapped in perineural nets. Scientists have also discovered that there is a direct mathematical relationship between brain organization and behavior. The rats with the highest number of cells wrapped in these active webs were the ones that chose the least amount of large rewards.
These findings suggest that psilocybin enhances the function of specific inhibitory cells in the prefrontal cortex. Because these cells act to suppress other brain signals, their increased activity is thought to reduce the amount of brain pathways that drive reward-seeking behavior. “Our results suggest that psilocybin reduces incentive motivation,” Del Arco said. “We believe that psilocybin reduces the value that animals assign to reward cues, thereby reducing their motivation to pursue the reward.”
“Our results also suggest that these changes in motivation are associated with long-term changes in the activity of parvalbumin-inhibitory interneurons in the prefrontal cortex,” del Arco added. “The prefrontal cortex controls reward-seeking behavior and drug taking.”
“The key message is that psilocybin changes how the brain processes reward cues and may ultimately reduce reward motivation,” Del Arco said. “These findings provide new insights into the mechanisms by which psilocybin may be a useful treatment for drug abuse and relapse.”
Although the study provides new insights into the brain, the authors note some limitations that should be considered. The behavioral task was primarily designed to measure choice impulsivity rather than pure motivation. “Keep in mind that we are talking about basic research,” Del Arco cautioned. “Our study does not prove that psilocybin is a good treatment for drug abuse. At this point, we are only investigating the drug’s potential mechanism of action in the brain.”
Also, this experiment only included male rats, meaning the study results may not apply equally to female animals. Biological sex can influence how psychedelic compounds interact with brain chemistry and brain behavior. Commenting on the implications of the findings, Professor Del Arco said: “The effects are large but moderate. We think our study points the way for future studies to identify new mechanisms of psilocybin in the brain reward system.”
The definition of long-term effects in this study is limited to 48 hours. This represents a lasting change compared to the immediate effects of the drug, but does not capture changes that can last for weeks or months. “We are currently conducting follow-up studies using different behavioral paradigms to provide proof of concept for psilocybin altering incentive motivation,” Del Arco said. “Our long-term goal is to identify the long-term mechanisms of psilocybin in the brain’s reward system.”
“Research collaboration was important in this study, as in other scientific fields,” DelArco added. “Our study involved a variety of laboratories and techniques that provide a more complete picture of psilocybin’s effects on the brain, from plasticity to behavior.”
The study, “Psilocybin reduces preference for large rewards with increased activity of parvalbumin neurons with perineuronal networks in the medial prefrontal cortex,” was authored by Jenna Hoff, Andrew Williams, Obie Allen IV, Barbara Zisabella, Harry Pantazopoulos, and Alberto Del Arco.
