McLean Study Identifies Critical Brain Areas Involved in Stress and Anxiety

Discovery may lead to more targeted treatments

April 04, 2006

Public Affairs
Adriana Bobinchock

Belmont, MA - Researchers at Harvard Medical School affiliate McLean Hospital have discovered what they believe to be a principal brain mechanism leading to a heightened state of anxiety and possibly, depression.

The finding, published in the April 5 issue of the Journal of Neuroscience (PubMed), has the potential to help the more than 45 million of American adults who suffer from anxiety and depression each year, says lead author Edward Meloni, PhD.

Meloni and his team reported on their ability to neutralize the effects of anxiety by preventing a chemical reaction in the brain using an experimental drug called a D1 antagonist, which blocks the neurotransmitter dopamine at a specific receptor subtype known as D1. This is the first time that researchers have been able to identify dopamine as a likely culprit in amplifying the response to stress, an advance that could have important implications for those suffering from anxiety disorders and certain types of depression.

"Dopamine has been around forever and while these D1 antagonists are only slightly newer, nobody has put the two together until now," says Meloni. "This finding will allow us to concentrate on a new area of treatment for anxiety and could lead to better functioning medications."

The newly identified dopamine pathway also involves a brain chemical called corticotropin-releasing factor (CRF). CRF has been found in high amounts in people with some types of anxiety and depression, and a rise in CRF levels has been shown previously to put rats into a heightened state of anxiety. Not known, however, was the trigger causing this flood of CRF into the central nervous system following a stressful event ultimately resulting in jitters, increased heart rate and fast breathing. It turns out dopamine might be the chemical switch.

Using a novel approach, Meloni' s team measured the normal startle response to a stressful noise in a large group of rats. The investigators administered CRF to the rats, increasing their state of anxiety and making them even more jumpy, similar to what has been observed in humans who suffer from some forms of anxiety.

The team then gave varying doses of the D1 antagonist drug, which proceeded to block only the D1 subtype of dopamine receptors. The results were astounding because the drug allowed the rats to return to a normal state, without any effect on their baseline startle response.

"This is critical because the rats could function normally and react to a perceived fear, but the D1 antagonist simply blocked the ability of the extra CRF to heighten anxiety. This is the first demonstration that systems involved in CRF-generated anxiety and stress can be reduced by blocking a certain class of dopamine receptors," says Meloni.

The team also examined the brain pathways that might be involved in causing these effects. They found that CRF neurons in the bed nucleus, one of the brain' s anxiety centers, are completely covered with dopamine terminals, suggesting that dopamine systems communicate with CRF neurons and control their function. This sets up important implications for ultimately controlling mood, according to Meloni.

"We think we have discovered a novel interaction between dopamine and stress molecules. We believe if you can manipulate the dopamine system via this pathway, then you can control what the CRF system is doing, and it is the CRF system that drives anxiety and stress responses," says Meloni.

These results are opening new avenues for future research, including testing with D1 antagonists in people with anxiety and/or depression. Meloni also hopes to use animal models to learn whether this brain circuit is more susceptible to trauma and stressors in early development that could predispose an individual to anxiety disorders and depression in adulthood.

"It may be that child abuse or early trauma could cause the dopamine-CRF interaction to break down, which could lead to anxiety disorders and possibly depression in adulthood," adds Meloni. His team is continuing this research to better understand the connection between dopamine and CRF, with the hopes of eventually developing early interventions and treatment for debilitating psychiatric disorders.

McLean Hospital, consistently ranked the nation's top psychiatric hospital by U.S. News & World Report, is an affiliate of Harvard Medical School and Massachusetts General Hospital, and a member of Partners HealthCare.

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