Summary: A new study provides novel mechanistic insights into how ketamine exerts its antidepressant effects for those with depression.
Source: Karolinska Institute
According to the World Health Organization, depression is a leading cause of disability worldwide and the disease affects more than 360 million people every year.
The risk of suffering is affected by both genetics and environmental factors. The most commonly prescribed antidepressants, such as SSRIs, affect nerve signalling via monoamines in the brain. However, it can take a long time for these drugs to help, and over 30 percent of sufferers experience no relief at all.
The need for new types of antidepressants with faster action and wider effect is therefore considerable. An important breakthrough is the anaesthetic ketamine, which has been registered for some years in the form of a nasal spray for the treatment of intractable depression.
Unlike classic antidepressants, ketamine affects the nerve signalling that occurs via the glutamate system, but it is unclear exactly how the antidepressant effect is mediated. When the medicine has an effect, it relieves depressive symptoms and suicidal thoughts very quickly.
However, ketamine can cause unwanted side effects such as hallucinations and delusions and there may be a risk of abuse so alternative medicines are needed. The researchers want to better understand how ketamine works in order to find substances that can have the same rapid effect but without the side effects.
In a new study, researchers at Karolinska Institutet have further investigated the molecular mechanisms underlying ketamine’s antidepressant effects. Using experiments on both cells and mice, the researchers were able to show that ketamine reduced so-called presynaptic activity and the persistent release of the neurotransmitter glutamate.
“Elevated glutamate release has been linked to stress, depression and other mood disorders, so lowered glutamate levels may explain some of the effects of ketamine,” says Per Svenningsson, professor at the Department of Clinical Neuroscience, Karolinska Institutet, and the study’s last author.
When nerve signals are transmitted, the transmission from one neuron to the next occurs via synapses, a small gap where the two neurons meet.
The researchers were able to see that ketamine directly stimulated AMPA receptors, which sit postsynaptically, that is, the part of the nerve cell that receives signals and this leads to the increased release of the neurotransmitter adenosine which inhibits presynaptic glutamate release.
The effects of ketamine could be counteracted by the researchers inhibiting presynaptic adenosine A1 receptors.
“This suggests that the antidepressant action of ketamine can be regulated by a feedback mechanism. It is new knowledge that can explain some of the rapid effects of ketamine,” says Per Svenningsson
In collaboration with Rockefeller University, the same research group has also recently reported on the disease mechanism in depression.
The findings, also published in the journal Molecular Psychiatry, show how the molecule p11 plays an important role in the onset of depression by affecting cells sitting on the surface of the brain cavity, ependymal cells, and the flow of cerebrospinal fluid.
About this psychopharmacology research news
Author: Press Office
Source: Karolinska Institute
Contact: Press Office – Karolinska Institute
Image: The image is in the public domain
Original Research: Open access.
“Ketamine decreases neuronally released glutamate via retrograde stimulation of presynaptic adenosine A1 receptors” by Vesna Lazarevic, Yunting Yang, Ivana Flais & Per Svenningsson. Molecular Psychiatry
Abstract
Ketamine decreases neuronally released glutamate via retrograde stimulation of presynaptic adenosine A1 receptors
Ketamine produces a rapid antidepressant response in patients with major depressive disorder (MDD), but the underlying mechanisms appear multifaceted. One hypothesis, proposes that by antagonizing NMDA receptors on GABAergic interneurons, ketamine disinhibits afferens to glutamatergic principal neurons and increases extracellular glutamate levels.
However, ketamine seems also to reduce rapid glutamate release at some synapses. Therefore, clinical studies in MDD patients have stressed the need to identify mechanisms whereby ketamine decreases presynaptic activity and glutamate release.
In the present study, the effect of ketamine and its antidepressant metabolite, (2R,6R)-HNK, on neuronally derived glutamate release was examined in rodents. We used FAST methodology to measure depolarization-evoked extracellular glutamate levels in vivo in freely moving or anesthetized animals, synaptosomes to detect synaptic recycling ex vivo and primary cortical neurons to perform functional imaging and to examine intracellular signaling in vitro.
In all these versatile approaches, ketamine and (2R,6R)-HNK reduced glutamate release in a manner which could be blocked by AMPA receptor antagonism. Antagonism of adenosine A1 receptors, which are almost exclusively expressed at nerve terminals, also counteracted ketamine’s effect on glutamate release and presynaptic activity. Signal transduction studies in primary neuronal cultures demonstrated that ketamine reduced P-T286-CamKII and P-S9-Synapsin, which correlated with decreased synaptic vesicle recycling. Moreover, systemic administration of A1R antagonist counteracted the antidepressant-like actions of ketamine and (2R,6R)-HNK in the forced swim test.
To conclude, by studying neuronally released glutamate, we identified a novel retrograde adenosinergic feedback mechanism that mediate inhibitory actions of ketamine on glutamate release that may contribute to its rapid antidepressant action.
