Understanding the brain-specific effects of ketamine could lead to better antidepressants

Thank you. Listen to this article using the player above. ✖

Researchers at Zhejiang University have uncovered the mechanistic basis for the rapid antidepressant effects of ketamine. Published in ScienceThis study is promising for the development of more effective antidepressants.

Conventional antidepressants take several weeks to take effect

Depressive disorders, commonly referred to as depression, affect about 280 million people all over the world. This mental health condition is characterized by a persistently depressed mood and a reduced interest or pleasure in activities. In severe cases, depression can lead to suicide and 700,000 people yearly.

Current treatments for depression include psychotherapy and antidepressants such as selective serotonin reuptake inhibitors. Traditional antidepressants can provide relief for some patients, but it often takes several weeks for these medications to work.

Ketamine is a psychedelic drug known for its analgesic, dissociative and euphoric effects. Although it has long been used as an anesthetic in hospitals and veterinary clinics, ketamine has recently gained attention due to its rapid and sustained antidepressant effects. In 2019A prescription version of ketamine, called esketamine (Spravato), has been approved by the U.S. Food and Drug Administration (FDA) to treat treatment-resistant depression. This drug acts as a non-competitive antagonist of the N-methyl-D-aspartate receptor (NMDAR), a mechanism that is thought to contribute to its antidepressant properties, although the exact mechanism remains unclear.

Ketamine has a brain region-specific effect

Because NMDAR is expressed throughout the brain, it is unclear whether ketamine acts on many brain regions simultaneously or whether it targets one or a few primary sites that trigger a signaling cascade. Previous studies The use of animal models of depression has shown that the lateral habenula (LHb), also called the “anti-reward center” of the brain, plays a role in both the development of depression and the mechanism of action of ketamine due to the observed hyperactivity of NMDARs.

To study the mode of action of ketamine, mouse models were subjected to chronic stress to induce a depression-like state. They were then injected with either saline or ketamine. NMDAR-mediated synaptic currents were measured in the LHb and hippocampal neurons. One hour after injection, brain slices were prepared and analyzed using in vitro Slice electrophysiology. In vivo Tetrode recordings were also performed to determine the basal firing rate and burst rate in neurons from both brain regions.

The in vitro Experiments showed that a single systemic ketamine injection specifically blocked NMDAR currents in the LHb neurons, but not in the hippocampal neurons. in vivo Recordings also supported this result and showed that the basal firing rate and burst rate in the neurons of the LHb were much higher than in those of the hippocampus. The neuronal activity of the LHb was also significantly suppressed within a few minutes after ketamine injection.

The researchers suspected that this effect occurs because ketamine is a use-dependent blocker – that is, it only inhibits NMDARs when they are in an open activated state – since LHb neurons have increased activity in the depressed state than hippocampal neurons. By altering the activity levels of neurons in both the hippocampus and LHb, the researchers were able to alter the sensitivity of each region to ketamine.

Conditional knockouts of NMDARs in the LHb also prevented the antidepressant effects of ketamine by blocking the systemic ketamine-induced increase in serotonin and brain-derived neurotrophic factor in the hippocampus.

Development of effective antidepressants

Ketamine likely affects multiple brain regions to produce its antidepressant effects, but to understand how the drug produces its full effects, it is important to understand the timing of involvement of these regions.

“We suspect that neurons in different brain regions may be recruited at different stages and that an LHb-NMDAR-dependent event likely occurs further up the ketamine signaling cascade. in vivo,” the authors wrote in the newspaper.

“Overall, these primary/direct and secondary/indirect changes in different brain regions could work together to trigger the full spectrum of long-term effects of ketamine,” says wrote.

“This distinction between ketamine’s primary and secondary targets in the brain should aid in the development of more precise and effective antidepressant treatments,” the authors say. completed.

Reference: Chen M, Ma S, Liu H et al. Brain region-specific effects of ketamine as a rapid antidepressant. Science. 2024. doi: 10.1126/science.ado7010

This article is a revision of a Press release from American Association for the Advancement of Science. The material has been edited for length and content.