Amphetamine scrambles the brain’s sense of time by degrading prefrontal neuron coordination

A new study published in Neuropharmacology sheds light on how amphetamine, a stimulant often misused and prescribed to treat attention-related conditions, affects brain activity linked to executive control. Researchers found that a single dose of amphetamine disrupted mice’s ability to judge time accurately by altering how neurons in the prefrontal cortex represent time. The findings suggest that amphetamine impairs cognitive functions by increasing the variability of neural signals that encode time, a core component of decision-making and attention.

Amphetamine is a powerful stimulant that increases levels of chemicals like dopamine and norepinephrine in the brain. While it can temporarily enhance focus or alertness, it also has well-documented side effects, especially when taken in high doses or without medical supervision. One area of concern is its effect on executive functions—higher-order processes that include planning, attention, and self-control. The prefrontal cortex, a brain region involved in these functions, has been shown to be especially sensitive to changes in dopamine levels, which are significantly affected by amphetamine use.

The new study, led by Matthew Weber and Nandakumar Narayanan at the University of Iowa, sought to better understand how amphetamine affects brain activity during tasks requiring executive control.

“Amphetamine is a commonly abused drug that causes dopamine to be released from neurons and prevents reuptake of dopamine. We know that amphetamine can have a huge impact on cognitive function, but it is unknown why or how. We conducted this study to investigate basic mechanisms of how amphetamine affects cognitive function,” said Narayanan, Juanita J. Bartlett Professor and director of the Center for Neurodegeneration at the University of Iowa.

To investigate this, the researchers turned to interval timing—a behavioral task in which animals must estimate time intervals of several seconds to earn a reward. Interval timing is widely used in both animal and human research because it depends on the prefrontal cortex and requires attention and working memory. Importantly, this task provides a way to measure not only how accurate a subject is in judging time but also how consistent their judgments are from trial to trial.

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The research team approached this question in two parts. First, they conducted a meta-analysis of 15 previously published rodent studies on amphetamine and interval timing. They found that amphetamine had a significant effect on timing precision, making animals’ estimates of time more variable. While it also had an effect on timing accuracy—whether the timing was generally early or late—the impact on variability was stronger. These findings established a reliable link between amphetamine use and disrupted temporal judgment.

Next, the team conducted their own experiment using mice trained on a well-established version of the interval timing task. The mice were taught to switch between two response ports based on how much time had passed, with rewards given for correct timing. After several weeks of training, the researchers implanted electrodes in the mice’s prefrontal cortex to monitor the activity of individual neurons during the task. On the first day, the mice received a saline injection before the task, serving as a baseline. On the second day, they were given an injection of amphetamine before performing the same task again.

Behaviorally, the mice showed increased variability in their timing after receiving amphetamine. Although their average timing shifted slightly earlier, the more noticeable effect was the inconsistency in when they made their decisions. This change echoed the results of the earlier meta-analysis and suggested that amphetamine made it harder for the mice to maintain steady estimates of time across trials.

At the neural level, the researchers focused on patterns of activity known as “ramping”—gradual changes in firing rates of neurons that occur during the timed interval. This kind of activity is thought to reflect how the brain keeps track of time. Under normal conditions, many prefrontal neurons show a steady increase or decrease in activity during the interval. However, after amphetamine was administered, this ramping activity became significantly more variable. The average rate of firing didn’t change, but the consistency of the ramping pattern from trial to trial did. This suggests that the brain’s internal clock was no longer functioning reliably.

“We guessed that amphetamine would impair brain function, but we were surprised that amphetamine disrupted how these neurons work together,” Narayanan told PsyPost. “We can measure how neurons work together and found that amphetamine weakened these interactions. This provides fresh insight into how neurons in the prefrontal cortex cooperate and how amphetamine degrades this cooperation.”

The researchers also found that the coordination between neurons was weakened after amphetamine exposure. Neurons that normally showed synchronized activity during the task became less functionally connected. Using joint activity measurements between pairs of neurons, the researchers showed that the cooperative firing patterns seen under normal conditions were diminished when the drug was introduced. These weakened interactions may reflect a breakdown in the neural networks that support complex timing and decision-making processes.

Another key finding involved low-frequency brain rhythms in the 2–5 Hz range, often linked to cognitive control and attention. These oscillations were noticeably reduced in the prefrontal cortex after amphetamine administration. Prior research has suggested that such brain rhythms play an important role in organizing neural activity during tasks that require sustained focus or timing. Their disruption may further explain the loss of precision observed in the behavioral data.

Taken together, the results provide strong evidence that amphetamine affects how the brain processes time by disrupting the consistency and coordination of neural activity in the prefrontal cortex. The effects were observed after a single dose of the drug, indicating that even acute exposure can interfere with core aspects of executive function.

“We focused on a simple cognitive behavior—timing intervals of a few seconds, which helps guide our everyday interactions with the world,” Narayanan explained. “Our study, which was in rodents and focused on the prefrontal cortex, offers a unique glimpse into how amphetamine affects this cognitive behavior. We believe that this is relevant for understanding drugs of abuse, treatments, and also diseases like Parkinson’s disease and schizophrenia that involve dopamine.”

As with any study, there are limitations to consider. First, while the dose used was consistent with previous studies, it reflects the higher end of the range used in rodent research and may not correspond precisely to typical human use. Second, the drug was administered systemically, affecting the entire brain. Although the researchers focused on the prefrontal cortex, amphetamine also impacts other regions such as the striatum, which is involved in timing accuracy. Future research will be needed to isolate the specific contributions of different brain areas and neurotransmitter systems to the observed behavioral changes.

Another limitation is that the study only examined the effects of a single dose. It is still unclear how repeated or chronic use of amphetamine might influence temporal processing and neural coordination over time. The researchers suggest that future studies could combine this type of neural recording with techniques that allow more precise manipulation of brain circuits, such as optogenetics, to better understand the causal relationship between neuronal variability and timing behavior.

“Our study was in rodents, so we have to be careful when translating our results to humans,” Narayanan noted. “However, the reason that we study timing behavior is that all mammals, from rodents to humans, have similar brain processes that help guide our actions in time.”

“Amphetamine is a complex drug that affects many different regions of the brain. We are studying how other brain areas are involved and developing much more specific methods to investigate how amphetamine affects cognitive function.”

“Our goal is to learn how dopamine affects the neural circuitry of cognition,” Narayanan added. “Through hard work and rigorous science, this knowledge will lead to new biomarkers, and maybe even new treatments for diseases that impair cognition.”

“The only way we develop new knowledge like this is through careful and rigorous science—we’d like to thank the American public and the National Institutes of Health for funding this work. We hope to keep working on this problem to come up with a better understanding of, and better treatments for, amphetamine addiction, ADHD, Parkinson’s disease, and schizophrenia.”

The study, “Amphetamine increases timing variability by degrading prefrontal temporal encoding,” was authored by Matthew A. Weber, Kartik Sivakumar, Braedon Q. Kirkpatrick, Hannah R. Stutt, Ervina E. Tabakovic, Alexandra S. Bova, Young-cho Kim, and Nandakumar S. Narayanan.