Ketamine is a drug that has diverse clinical applications, but is also used illicitly as a recreational drug with dissociative effects. The impact of prolonged exposure to ketamine on the brain isn’t well understood, but researchers at Columbia University have now mapped ketamine’s effects on the brains of mice, and found that repeated use over extended periods of time leads to widespread structural changes in the brain’s dopamine (DA) system. The findings, they suggest, bolster the case for developing ketamine therapies that target specific areas of the brain, rather than administering doses that wash the entire brain in the drug.

“Instead of bathing the entire brain in ketamine, as most therapies now do, our whole brain mapping data indicates that a safer approach would be to target specific parts of the brain with it, so as to minimize unintended effects on other dopamine regions of the brain,” said Raju Tomer, PhD, who is senior author of the team’s published paper in Cell Reports. In their report, titled “Whole-brain mapping reveals the divergent impact of ketamine on the dopamine system,” the team concluded, “The finding that ketamine exposure leads to divergent alterations in specific brain regions, rather than a uniform activating impact, is particularly intriguing and could have significant implications for the development of treatments for depression, schizophrenia, and psychosis.”

“Ketamine is a multifunctional drug with clinical applications as an anesthetic, pain management medication, and a fast-acting antidepressant,” the authors wrote. However, it is also recreationally abused for its dissociative effects. Most studies of ketamine’s effects on the brain to-date have looked at the effects of acute exposure—how one dose affects the brain in the immediate term. But, as the team noted, while recent studies in rodents are revealing the neuronal mechanisms mediating its actions, “…  the long-term impact of chronic ketamine exposure on brain networks remains much less understood, with profound scientific and clinical implications.”

As they pointed out, the antidepressant effect of ketamine is known to be transient, necessitating long-term maintenance treatments, while recreational abuse at higher doses has been linked to cognitive and sensory impairments, as well as significant brain damage. “Therefore, given its broad clinical importance and increasing long-term abuse potential at higher doses, there is a considerable interest in understanding the molecular, cellular, and neural circuit adaptations caused by long-term exposure to ketamine over a wide range of doses.”

For their newly reported study the researchers developed a subcellular, high-resolution whole brain phenotyping approach, including data analysis methods, which they used to examine the effects on the entire dopaminergic system of male mice, of repeated daily exposure ketamine over the course of up to ten days. The team assessed the effects of repeated exposure at two doses of the drug, one analogous to the dose used to model depression treatment in mice, and another closer to the dose that would induce anesthesia.

The results showed that statistically significant alterations to the brain’s dopamine makeup were only measurably detectable after ten days of daily ketamine use, but the drug’s effects on dopamine system were visible at both doses.

More specifically, the study found that repeated ketamine exposure lead to a decrease in dopamine neurons in regions of the midbrain that are linked to regulating mood, as well as an increase in dopamine neurons in the hypothalamus, which regulates the body’s basic functions like metabolism and homeostasis. “We found that chronic ketamine exposure leads to a dosage-dependent decrease in DA neurons counts within midbrain regions related to behavior state and increase within hypothalamic domains …” they wrote.

The former finding, that ketamine decreases dopamine in the midbrain, may indicate why long-term abuse of ketamine could cause users to exhibit similar symptoms to people with schizophrenia, a mood disorder. The latter finding, that ketamine increases dopamine in the parts of the brain that regulate metabolism, on the other hand, may help explain why it shows promise in treating eating disorders.

The researchers’ highly detailed data also enabled them to track how ketamine affects dopamine networks across the brain. They found that ketamine reduced the density of TH+ dopamine axons, or nerve fibers, in the areas of the brain responsible for our hearing and vision, while increasing dopamine axons in the brain’s cognitive centers. These intriguing findings may help explain the dissociative behavioral effects observed in individuals exposed to ketamine. In their paper, they noted, “Overall, consistent with the divergent changes in TH+ neuron counts in the midbrain and hypothalamic dopaminergic domains, chronic ketamine exposure resulted in increased TH+ neuronal projection densities in the associative brain centers, including PFC-related regions, and decreased innervations in regions involved in visual, auditory, and spatial information processing.”

Co-author Malika Datta, PhD, stated, “The restructuring of the brain’s dopamine system that we see after repeated ketamine use may be linked to cognitive behavioral changes over time.” Co-author Yannan Chen, PhD added “The study is charting a new technological frontier in how to conduct high-resolution studies of the entire brain.”

The team claims the reported study represents the first successful attempt to map changes induced by chronic ketamine exposure at subcellular resolution, down to the level of seeing ketamine’s effects on parts of individual cells.

Most subcellular studies of ketamine’s effects conducted to-date have been hypothesis-driven investigations of one area of the brain that researchers have targeted because they believed that it might play an important role in how the brain metabolizes the drug. Tomer et al’s work represents the first subcellular study to examine the entire brain without first forming such a hypothesis.

“This study gives us a deeper brain-wide perspective of how ketamine functions that we hope will contribute to improved uses of this highly promising drug in various clinical settings as well as help minimize its recreational abuse,” Tomer said. ”More broadly, the study demonstrates that the same type of neurons located in different brain regions can be affected differently by the same drug.”

Noting limitations of their study, the researchers also suggested the need for further study and targeted treatment approaches. “… such non-monolithic brain-wide impact further underscores the need for unbiased investigations of on/off-target effects of ketamine treatment at a range of doses, as well as the urgency to develop targeted pharmacological intervention approaches (e.g., focused ultrasound-based approaches) for treatment of complex brain disorders.”

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