Model of ketamine molecule. Image credit: Public domain (CC0)
Over 264 million people around the world suffer from depression, according to the World Health Organization (WHO). Depression can be debilitating, and while anti-depressant drugs are available, they do not always work. A small molecule drug mainly used for anesthesia called ketamine has recently been shown to ameliorate depressive symptoms within hours, much faster than most anti-depressants. However, the molecular mechanisms behind this effect are still largely unknown.
Most anti-depressant drugs work by restoring the normal balance of dopamine and other chemical messengers in the brain. Dopamine is released by a specialized group of cells called dopaminergic neurons, and helps us make decisions by influencing a wide range of other cells in the brain. In a healthy brain, dopamine directs us to rewarding choices, while avoiding actions with negative outcomes. During depression, these dopamine signals are perturbed, resulting in reduced motivation and pleasure. But it remained unclear whether ketamine’s anti-depressant activity also relied on dopamine.
To investigate this, Wu et al. used a behavioral study called “learned helplessness” which simulates depression by putting mice in unavoidable stressful situations. Over time the mice learn that their actions do not change the outcome and eventually stop trying to escape from unpleasant situations, even if they are avoidable. The experiment showed that dopaminergic neurons in an area of the brain that is an important part of the “reward and aversion” system became less sensitive to unpleasant stimuli following learned helplessness. When the mice received ketamine, these neurons recovered after a few hours.
Individual mice also responded differently to ketamine. The most ‘resilient’, stress-resistant mice, which had distinct patterns of dopamine signaling, also responded most strongly to the drug. Genetic and chemical manipulation of dopaminergic neurons confirmed that ketamine needed intact dopamine signals to work, and revealed that it acted indirectly on dopamine dynamics via another brain region called the medial prefrontal cortex.
These results shed new light on how a promising new anti-depressant works. In the future, they may also explain why drugs like ketamine work better for some people than others, ultimately helping clinicians select the most effective treatment for individual patients.
