A Key to Turning Off Stress

Researchers identify a pathway that leads to pressure-cooker feelings and find a drug that can tamp down the brain’s response

Jamie Maguire

Busy lives do more than make our days a series of juggling acts. Stress has been found to cause depression, cardiovascular disease and infertility, among other disorders, so figuring out how to control stress would benefit millions. Biomedical researchers at Tufts have made some headway—and it doesn’t involve running away to a desert island.

Jamie Maguire, an assistant professor of neuroscience at the School of Medicine, and her colleagues have identified new pathways in the brain that are involved in the chemical chain reaction that leads to stress, and they have discovered that a drug used to treat male pattern baldness can tamp down that chemical response. The work could lead to new ways to treat stress-related illnesses.

Of course, stress isn’t always bad. When animals—and that includes you and me—are faced with danger, our fight-or-flight response is triggered, leading to rapid breathing and quickened heart rate. That stress response makes sense for a gazelle about to be a lion’s next meal: It sends more oxygenated blood to the muscles, allowing the gazelle to flee to safety.

In humans and our close primate relatives, the stress response also depresses biological processes that aren’t useful in an emergency, including digestive and sexual functions. It also triggers aggressive behavior and irritability, priming otherwise peaceful individuals for a fight.

But daily annoyances like traffic jams and deadlines have hijacked humans’ stress response. And, unlike a hungry lion, some of our more serious modern-day stressors, like unemployment or war, can persist for months or years. Over time, irritability, aggression, depressed digestion and sexual dysfunction undermine health and quality of life.

It’s All in Your Head

The fight-or-flight syndrome is orchestrated by a complex chemical cascade that starts with neurons deep in the brain. Those brain cells release a hormone, which kicks off a chain reaction that eventually stimulates the adrenal glands to dump corticosterone—the stress hormone responsible for the physiological and psychological changes associated with fight or flight—into the bloodstream.

Maguire and her team wanted to know more about that chemical cascade, especially the early stages that had not been well studied.

One way neurons in the brain communicate with each other is via neurotransmitters, chemical couriers that ferry messages between neurons. The best known neurotransmitter is serotonin, low levels of which are widely believed to play a role in depression. Maguire studies a lesser known neurotransmitter, called GABA, which has been implicated in mood disorders, panic and anxiety attacks, premenstrual syndrome and postpartum depression.  

In a study published in the Journal of Neuroscience in December, Maguire and her colleagues demonstrated that one particular step in the chain reaction that results in the stress response creates a brain chemical known as THDOC (if you must know, that’s tetrahydrodeoxycorticosterone). After the initial stress, THDOC makes the subset of neurons controlling the stress response even more excitable, acting on the brain using the same receptors GABA uses.

The team also found that the brain’s response to THDOC can be stopped in its tracks by the steroid-blocking drug finasteride, used to treat baldness in men. If the THDOC is not activated, then the stress-inducing corticosterone doesn’t get released into the bloodstream—and the panicky feeling we know as fight or flight evaporates.

“There hasn’t been a lot of work done on controlling the stress response, so this [research] gave us a lot of information,” says Maguire, who will continue her research to determine on which receptors in the brain THDOC works.

“If we can identify the specific receptors, then we can target them to regulate the stress response, and maybe we can prevent the pathological consequences of stress,” she says.

Jacqueline Mitchell can be reached at jacqueline.mitchell@tufts.edu.


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