A recent study on anxiety examined the role of the neurotransmitter glutamate; the findings could help scientists develop more effective interventions.

Almost everybody experiences anxiety in one of its forms. Over time, evolution honed anxiety as a survival mechanism; it forms part of our "fight-or-flight" response. The heart pumps a little faster, and there might be a sensation of nausea as the body prepares for action.

Although anxiety is a natural response, it can spiral out of control for some people. Rather than being a protective force that helps us navigate everyday life, it becomes a burden that impacts well-being. Also, being more prone to anxiety increases the risk of developing an anxiety disorder and depression.

Beyond mental health, anxiety might also have physical effects; the authors of the new study write that sustained high levels of anxiety "may increase the risk of developing cardiovascular disease." The Anxiety and Depression Association of America say that anxiety disorders impact almost 1 in 5 adults in the US each year.

Anxiety disorders are as common as depression, but until relatively recently, they received much less attention. Because of anxiety's growing prevalence, the neurological mechanisms that are involved are being investigated. The latest study, which now appears in The Journal of Neuroscience, investigates the role of glutamate in the hippocampus.

What is glutamate?

Glutamate is an amino acid and the primary excitatory neurotransmitter in the brain. In recent years, studies have hinted that glutamate might be involved in anxiety. Reductions in glutamate activity seem to increase anxious behavior, and glutamate levels within the hippocampus—which is the part of the brain primarily involved in regulating emotions and memory—seem particularly important. Earlier studies have also concluded that two other regions of the brain work with the hippocampus to modulate anxiety; called area 25 and area 32, these regions form part of the prefrontal cortex.

However, our understanding of glutamate's role in anxiety is not fully formed, and other studies have produced conflicting results. As an example, a study using nonanxious rats found that a reduction of activity at some glutamate receptor subtypes in the hippocampus actually reduced levels of anxiety. The authors of the latest study wanted to examine the role of glutamate in anxiety in more detail. To get a clearer picture, they ran a series of experiments on marmosets.

Glutamate and anxiety in primates

First, the team tested each marmoset's anxiety levels when introduced to an unfamiliar human (one of their handlers wearing a mask). As expected, the animals with the greatest levels of anxiety—or high-trait anxiety—had significantly lower levels of glutamate in their hippocampus. High-trait anxiety correlated with glutamate levels in the right anterior hippocampus.

Next, they artificially increased the level of glutamate in the highly anxious marmosets. They found that once glutamate levels reached normal levels, the animals responded less anxiously in psychological tests. This second arm of the experiment gave the researchers evidence of a causal relationship: Anxious primates naturally had lower levels of glutamate activity, and when glutamate was increased in the anxious primates' hippocampi, anxiety was reduced.

To gain more information about the role of brain areas 25 and 32, the team carried out further experiments. Blocking activity in these regions, they found that the anti-anxiety effects of increasing glutamate were abolished when area 25 was out of action. Blocking area 32, however, did not make a difference. The study authors suggest that the hippocampal-area 25 pathway could be an interesting target for future pharmaceutical interventions. Overall, the authors outline their conclusions:

"These findings provide causal evidence in primates that hippocampal glutamatergic hypofunction regulates endogenous high-trait anxiety, and the hippocampal-area 25 circuit is a potential therapeutic target."

Though scientists are still determining glutamate's role in anxiety, studies such as this bring us closer to a full understanding.