Low-Dose Ketamine Improves Social Impairments via Brain Region Restoration

A recent study from Osaka University that was published in Molecular Psychiatry revealed that a common anesthetic called ketamine, in low doses, can improve social impairments by restoring functioning in a specific brain region called the anterior insular cortex. The study was conducted using a mouse model of depression. 

Although ketamine is frequently used in small dosages to treat depression, little is known about how it works in the brain. In general, the term “ketamine” describes a combination of the two distinct ketamine forms, (S)-ketamine and (R)-ketamine. Despite having the identical chemical formula, these two molecules are mirror isomers, or enantiomers, because their three-dimensional structures are mirror reflections of one another. Even though they are typically found in pairs, they can also be divided into (S)- and (R)-ketamine. All are helpful in the treatment of depression; however their precise effects differ. 

The research team had to choose a suitable model before deciding to examine the effects of (S)- and (R)-ketamine on mice’s depression-like symptoms. They used a chronic (at least 6 weeks) social isolation mouse model because prolonged social isolation can cause depression and social deficits.  

Then, following behavioral testing, the researchers employed a technique that enabled them to compare neuronal activation throughout the entire brains of mice given with (S)-ketamine, (R)-ketamine, or saline (as a control).  

“In this way, we were able to observe differences between (S)-ketamine and (R)-ketamine treatments in terms of neuronal activation across the whole brain, without having a predefined hypothesis,” Rei Yokoyama, the study’s lead author, states “Notably, we found that chronic social isolation led to decreased neuronal activation in the anterior insular cortex—a brain region that is important for emotional regulation—during social contact, and that (R)-ketamine, but not (S)-ketamine, reversed this effect.” 
In a social memory test, the researchers also discovered that mice given (R)-ketamine performed better than mice not given the drug, suggesting enhanced social cognition. Furthermore, the benefits of (R)-ketamine vanished when neuronal activity in the anterior insular cortex was reduced.  

According to research senior author Hitoshi Hashimoto, “these results underscore the significance of the anterior insular cortex for the beneficial effects of (R)-ketamine on social impairments, at least in mice.” “Together, our results indicate that (R)-ketamine may be better than (S)-ketamine for improving social cognition, and they suggest that this effect is dependent on restoring neuronal activation in the anterior insular cortex.”  

These results are crucial since sadness and social isolation are becoming more commonplace around the globe. (R)-ketamine is a medication that shows promise for social deficits brought on by isolation and may improve the quality of life for those who suffer from related conditions. 

Journal Reference  

(R)-ketamine restores anterior insular cortex activity and cognitive deficits in social isolation-reared mice, Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02419-6