Why can new antidepressants be long-lasting and effective? Research Achievements of Zhejiang University Published in "Nature"

Why can new antidepressants be long-lasting and effective? On October 20th, the reporter learned from Zhejiang University that the team of the university published an article in the top international journal "Nature" on the evening of October 18th, solving this puzzle and providing new ideas for future clinical medication and new drug design.Ketamine trapping in the pore region of NMDA receptors

Why can new antidepressants be long-lasting and effective? On October 20th, the reporter learned from Zhejiang University that the team of the university published an article in the top international journal "Nature" on the evening of October 18th, solving this puzzle and providing new ideas for future clinical medication and new drug design.

Ketamine trapping in the pore region of NMDA receptors. Provided by the research group

Among numerous antidepressants, ketamine, as a new type of antidepressant that has emerged in recent years, has received great attention. It takes effect quickly and has long-lasting effects, and is considered by scientists to be the "most important discovery in the field of clinical psychiatry in the past half century".

Why can depression take effect quickly and have long-lasting effects when dealing with it?

Professor Hu Hailan's team from the School of Brain Science and Brain Medicine at Zhejiang University School of Medicine, who has been dedicated to the study of depression, published a long article in the top international journal "Nature" in 2018, revealing the mystery of how ketamine works quickly. Now, the team has provided an answer to the question of why ketamine has a particularly long-lasting effect.

There is a "reward center" in the human brain, and its level of activity affects emotions. In 2018, Hu Hailan's team found that there is a "counter reward center" in the brain - the lateral habenular nucleus, which plays an antagonistic and inhibitory role on the "reward center".

In a depressive state, neurons in the lateral habenular nucleus enter a special firing mode, which more strongly suppresses the "reward center" and leads to depressive emotions. The reason why ketamine can have a rapid antidepressant effect is precisely because it can effectively block the cluster discharge in this brain area, relieve its inhibition of the "reward center", and quickly improve emotions.

Can this mechanism explain the long-term effect of ketamine? This is the next scientific issue naturally arising from the work in 2018.

Hu Hailan's team conducted a large number of electrophysiological and behavioral experiments based on the previously established theoretical system of lateral habenular nucleus cluster discharge mediated depression, starting from behavioral and pharmacological perspectives.

We found that after 1 hour of injection in experimental mice, ketamine inhibited the NMDA receptor current in the lateral habenular nucleus by 80%. Surprisingly, after 24 hours of injection, there was still about 50% inhibition, "said Hu Hailan.

The glutamate receptor NMDAR is like the gatekeeper of a neuron, with a channel in the middle that allows calcium ions from outside the neuron to flow into the neuron. Previous studies have found that after binding to the receptor, ketamine is "embedded" in the "gate", as if it is "stuck" in this channel and cannot come out.

Perhaps it is precisely because ketamine 'gets stuck' in the glutamate receptor that affects its dissociation, avoiding the role of metabolic enzymes in the liver, that it can continue to function, "Hu Hailan said.

In response to this hypothesis, the team conducted a series of experiments to demonstrate that the long-term efficacy of ketamine is precisely due to its slow dissociation due to being "stuck" in the receptor.

Hu Hailan introduced that this study based on pharmacokinetics and pharmacodynamics reveals the unique pharmacochemical characteristics of ketamine, which not only provides theoretical guidance for achieving lower dose medication and more lasting efficacy in clinical practice, but also provides direction and basis for the transformation of new antidepressants. In the future, we may be able to extend the efficacy of ketamine by regulating the time it 'gets stuck' in the receptor, thereby reducing repeated administration

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