New Research Reveals What Happens After ‘Bathing the Entire Brain In Ketamine, As Most Therapies Now Do’
Ketamine, once notorious as an illicit recreational substance, has recently seen a shift in its reputation due to its emerging therapeutic benefits.
The medical community is now acknowledging its diverse medical applications.
This includes its use as an alternative to opioid painkillers and as a treatment for depression that doesn’t respond to conventional therapies.
A recent research paper in Cell Reports, conducted by a team of biologists and biomedical engineers from Columbia University, provides new insights into ketamine’s impact on the brain.
The study, which involved observing the brains of mice, revealed that prolonged and repeated use of ketamine causes significant changes in the brain’s dopamine system.
These discoveries support the development of more targeted ketamine treatments that focus on specific brain regions, instead of generalized brain exposure to the drug.
“Instead of bathing the entire brain in ketamine, as most therapies now do, our whole-brain mapping data,” according to senior author Rau Tomer, “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.”
The research revealed that repeated exposure to ketamine results in a reduction of dopamine neurons in certain midbrain areas related to mood regulation. Simultaneously, there’s an increase in dopamine neurons in the hypothalamus, which is crucial for controlling essential body functions like metabolism and homeostasis.
The decrease in dopamine in the midbrain could be a key factor in why long-term ketamine abuse might lead to symptoms resembling those of schizophrenia, a mood disorder.
Conversely, the increase in dopamine in brain areas governing metabolism could shed light on ketamine’s potential effectiveness in treating eating disorders.
Moreover, the study provided comprehensive data on the impact of ketamine on the brain’s dopamine networks. It was found that ketamine decreases the density of dopamine axons, which are nerve fibers, in regions associated with hearing and vision.
In contrast, it increases dopamine axons in areas involved in cognitive functions. These findings offer insights into the dissociative behaviors often seen in individuals who have been exposed to ketamine.
“The restructuring of the brain’s dopamine system that we see after repeated ketamine use,” says co-author Malika Datta, “may be linked to cognitive behavioral changes over time.”
Previous investigations into ketamine’s impact on the brain primarily focused on the immediate effects following a single dose. However, this study diverged by examining the effects of daily exposure to ketamine over up to ten days. Notable changes in the brain’s dopamine structure were only clearly observable after a consistent ten-day period of ketamine use.
The research team evaluated the impact of this repeated exposure using two different dosages: one mimicking the dose used in mice for modeling depression treatment, and the other similar to the amount used for anesthesia.
Remarkably, the influence on the dopamine system was evident at both dosage levels.
This study stands out as the first to successfully chart the changes caused by chronic ketamine exposure at an extremely fine level, known as “sub-cellular resolution.” This means observing the drug’s effects down to parts of individual cells.
Previously, sub-cellular studies on ketamine’s impact typically focused on specific brain areas hypothesized to be key in processing the drug. This research is the first sub-cellular study to examine the entire brain without first forming such a hypothesis.
Bradley Miller, a Columbia-based psychiatrist and neuroscientist specializing in depression, noted the study’s importance.
The expert explains: “Ketamine rapidly resolves depression in many patients with treatment resistant depression, and it is being investigated for longer term use to prevent the relapse of depression. This study reveals how ketamine rewires the brain with repeated use. This is an essential step for developing targeted treatments that effectively treat depression without some of the unwanted side effects of ketamine.”
The study was supported by the National Institutes of Health (NIH) and the National Institute of Mental Health (NIMH).
“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. More broadly, the study demonstrates that the same type of neurons located in different brain regions can be affected differently by the same drug,” adds Tomer.
Source:10.1016/j.celrep.2023.113491
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