Enhancing Depression Social Symptoms with Anesthetic

In a recent study published in Molecular Psychiatry, researchers from Osaka University used a mouse model of depression to show that one type of ketamine (a common anesthetic) in low doses can improve social impairments by restoring functioning in a specific brain region known as the anterior insular cortex.

Ketamine is commonly used in low dosages to treat depression, although its effects on the brain are uncertain. In general, ketamine refers to a combination of two types of ketamine: (S)-ketamine and (R)-ketamine. These two molecules are mirror isomers, also known as enantiomers; they share the same molecular formula, but their three-dimensional structures are mirror reflections of one another. Although they are typically found as (S) and (R) pairs, they can also be split into (S)-ketamine or (R)-ketamine. Each is effective in treating depression, albeit the specific effects differ.

When the study team chose to evaluate the effects of (S)-ketamine and (R)-ketamine on depression-like symptoms in mice, they needed to select an acceptable model. Given that long-term social isolation might cause depression and social deficits, they used a mouse model of chronic social isolation lasting at least 6 weeks.

The researchers next employed a way to directly evaluate neuronal activation over the entire brains of mice administered with (S)-ketamine, (R)-ketamine, or saline (as a control) immediately after behavioral testing.

“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,” says lead author of the study Rei Yokoyama. “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 discovered that mice given with (R)-ketamine performed better in recognizing strange mice than familiar mice, showing greater social cognition. Furthermore, when neuronal activity in the anterior insular cortex was inhibited, the (R)-ketamine-induced benefits vanished.

“These findings highlight the importance of the anterior insular cortex for the positive effects of (R)-ketamine on social impairments, at least in mice,” says Hitoshi Hashimoto, senior author of the study. “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.”

Given the rising global rates of social isolation and sadness, these findings are critical. (R)-ketamine is a promising treatment for isolation-induced social deficits that may improve the quality of life in people with related diseases.

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