A single dose of ketamine can treat depression in people for days to weeks, and we may be closer to understanding why. A study in mice shows the drug can become trapped inside certain receptors in the brain.
Most antidepressants, like selective serotonin reuptake inhibitors (SSRIs), must be taken daily for before people notice a benefit. A single dose of ketamine, on the other hand, alleviates depressive symptoms within 2 hours. These effects can last , even though blood levels of the drug rapidly decrease hours after use.
To understand why, at Zhejiang University in China and her colleagues examined ketamine鈥檚 effects on a brain region called the lateral habenula. This area is sometimes called the brain鈥檚 anti-reward centre. With depression, it becomes hyperactive.
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Hu and her team induced symptoms of depression in six mice by confining them to small enclosed spaces for a few hours each day for two weeks. The researchers injected half of them with ketamine and the rest with saltwater, then examined their brains the next day.
They found that, on average, only 24 per cent of lateral habenula neurons in the mice given ketamine showed heightened activity. In contrast, an average of 44 per cent of the same neurons were active in the mice given the placebo. This suggests that ketamine鈥檚 sustained antidepressant effects are due to the fact that it decreases lateral habenula activity.
Further experiments not only revealed how ketamine does this, but also helped explain why its effects are so long lasting. It turns out ketamine interacts with a type of receptor on lateral habenula neurons called an N-methyl-D-asparate (NMDA) receptor. These channels are like gates that open when neurons are stimulated. The researchers found that ketamine becomes trapped inside these gates as they shut, causing them to block the receptor. The drug only escapes when the gates reopen, which can be days later, says Hu. This suggests that if you could increase the number of NMDA receptors containing trapped ketamine, you could boost ketamine鈥檚 antidepressant effect.
So she and her colleagues stimulated lateral habenula neurons in mice after they received ketamine using a technique to switch cells on and off with light. A day later, these animals showed an even greater decrease in depressive symptoms than mice that received ketamine but not neuron stimulation. Hu says this further indicates ketamine鈥檚 sustained antidepressant effects are due to it becoming stuck inside NMDA receptors.
These findings provide 鈥渦nequivocal evidence that [ketamine鈥檚 effects] are NMDA receptor dependent鈥�, says at Vanderbilt University in Tennessee. Yet there are probably other contributing mechanisms, as ketamine affects many different areas of the brain, he says.
Nature
