Researchers have mapped the whole brain of mice, revealing how regular ketamine use produces divergent changes in specific areas of the brain responsible for producing the ‘feel-good’ neurotransmitter, dopamine. The discovery could have significant implications for the treatment of mental illness.
Because of its illicit use as a party drug, ketamine has had a bad rap for a while. But its reputation has been rehabilitated somewhat, with recent studies suggesting that the drug is an effective treatment for people with depression, especially those with a treatment-resistant form of the condition.
Many of these studies have looked at how a single dose of ketamine can be beneficial for mental health. Now, using high-resolution whole-brain mapping on mice, new research by Columbia University has revealed how repeated ketamine use over extended periods affects the brain’s dopamine system.
“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,” said Raju Tomer, the study’s corresponding author. “More broadly, the study demonstrates that the same type of neurons located in different brain regions can be affected differently by the same drug.”
Dopamine functions as a neurotransmitter, a chemical released by neurons to send signals to other nerve cells, and acts on areas of the brain to give feelings of pleasure, satisfaction, and motivation. The brain contains four major dopamine pathways.
The researchers generated high-resolution whole-brain images of mice, which they used to study the dose-dependent effects of daily ketamine exposure – 30 mg/kg and 100 mg/kg for one, five, and 10 days – on the brain’s entire dopamine system. They observed statistically significant neuronal changes only after 10 days of ketamine exposure for both 30 mg/kg and 100 mg/kg treatment groups.
In both groups, the researchers saw an overall dose-dependent decrease in dopamine neurons in midbrain regions related to mood regulation and, conversely, an overall increase within the hypothalamus, which regulates basic body functions like metabolism and homeostasis. Changes seen in the midbrain may explain why long-term abuse of ketamine can result in schizophrenia-like symptoms. Hypothalamic changes may help explain why ketamine has been found to be a promising treatment for eating disorders.
Tracking how ketamine affects dopamine networks across the brain, the researchers found that the drug reduced the density of dopamine axons, the impulse-conducting projections extending from a neuron, in brain areas responsible for hearing and sight, while increasing axons in the brain’s cognitive centers. This may explain the drug's dissociative effects, the feeling of being ‘detached’ from surroundings and disconnected from the body.
Given the divergent brain alterations produced by ketamine, the study’s findings suggest rethinking the way we currently use the drug and could have significant implications for the development of treatments for depression, schizophrenia and psychosis.
“Instead of bathing the entire brain in ketamine, as most therapies 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,” Tomer said.
The study was published in the journal Cell Reports.
Source: Columbia University