Scientists Find The Brain Region That Ketamine Likely Targets To Relieve Depression

Neural networks


Author: Kate Baggaley


Scientists have realized in recent years that the anesthetic ketamine, which is also a party drug, has a knack for fighting depression. But they didn't know much about how it worked. Now, in a mice study, researchers have zeroed in on the part of the brain that ketamine acts to alleviate depressive symptoms.

This gives researchers a better grounding in how ketamine combats depression, as well as more information about the disease itself. "A lot of what we are still struggling with in studies of psychiatric illnesses like depression is an understanding of the brain circuits involved," said Ronald Duman, a neuroscientist at the Yale University School of Medicine and coauthor of the new findings.

In the clinic, ketamine has long been used as an anesthetic and treatment for nerve pain. People also take it recreationally, capitalizing on its ability to distort perception and cause feelings of detachment or hallucinations. The drug seems to target a signaling network in the brain that is separate from those traditionally associated with depression. So it came as a surprise that ketamine could have yet another role, and potentially be an alternative for people with depression who don't respond well to standard medications. Moreover, antidepressant drugs often take weeks or even months to work, but ketamine appears to bring relief within hours.

"About half of patients either don't respond or become resistant to drugs over a period of years. And ketamine works in about 70 percent of those patients," said another team member, George Aghajanian.

Depressed people have lost many of the connections between neurons, or synapses, in their brains, Aghajanian said. "When they lose connections in the brain systems that are necessary to maintain normal mood states, that can lead to depression."

The researchers believe that ketamine restores the synaptic connections, at least temporarily. The idea is that ketamine increases the amount of neurotransmitter glutamate sloshing around in the brain, resulting in synaptic strengthening, Duman said.

Ketamine and the rat brain

To understand how ketamine triggers its antidepressant effects, Aghajanian and his colleagues injected small doses of the drug into different areas of rats' brains.

One region, the infralimbic prefrontal cortex, which has roles related to attention and mood, stood out. The region appeared to be the destination for ketamine — when the rats received infusions directly in this zone, they behaved like rats that had received doses of ketamine through their bloodstream (via an IV).

And when the researchers used a drug to block neurons in the infralimbic prefrontal cortex from firing, the ketamine stopped working. The rats had subpar coping skills compared to rodents on ketamine and showed behaviors linked to rodent's model of depression — they were quicker to give up on a swim test and more reluctant to venture out into exposed areas to eat.

"This informed us that this particular brain region was both sufficient and necessary for the behavioral effects of ketamine," said Duman.

Then the researchers used optogenetics, a method of controlling neurons with light, to see if they could emulate the effects of ketamine. When the team stimulated the infralimbic prefrontal cortex, the rats behaved as if on ketamine, and also had more synaptic connections.

This indicates that it's possible to come up with other approaches to imitate the benefits of ketamine, which sometimes has side effects including dissociative or "out of body" experiences.

A unique antidepressant

Ketamine does not work like other antidepressants, which mostly target receptors for the neurotransmitter serotonin or noradrenaline. Instead, ketamine affects another neurotransmitter called GABA. Duman and his colleagues believe that ketamine might briefly blocks neurons that release GABA, which hinders the release of another neurotransmitter, glutamate. By impeding GABA, ketamine allows a burst of glutamate that leads to an eruption of synapse rebuilding.

In future, the team wants to better understand this pathway. "We're continuing to characterize at a cellular level what is required or what triggers the antidepressant effect of ketamine, what triggers that burst of glutamate," said Duman, who published the findings today in Proceedings of the National Academy of Sciences.