Nearly one in five Americans have been diagnosed with some form of anxiety disorder. These range from panic attacks and post-traumatic stress disorder to social phobias and obsessive-compulsive disorders.
Anti-anxiety drugs or antidepressants can curb symptoms that interfere with day-to-day life. And these drugs are big business. In 2013, Americans filled 48 million prescriptions for the benzodiazepine drug alprazolam (Xanax). Patients also picked up 27 million prescriptions for sertraline (Zoloft), an antidepressant drug that also helps some people with anxiety.
Yet, while many people do find relief in these drugs, they don’t work for everyone. Benzodiazepines can interfere with normal thinking and induce drowsiness. They also can be highly addictive, so doctors are reluctant to prescribe them for people with a history of substance abuse. Zoloft and other selective serotonin reuptake inhibitors (SSRIs) also don’t work for everyone. They can cause nausea, jitters, insomnia, suicidal thoughts, and loss of libido.
However, researchers are teasing out another option for reducing anxiety. When stress kicks in, so would this experimental drug.
“By targeting specific enzymes,” said neuroscientist J. Megan Gray, “we can minimize side effects.”
Researchers from Calgary to Southern California are investigating the inner struggle between one brain chemical that keeps stress in check and another that is part of the body’s fight or flight response. Many of these investigators talked about their latest findings during the November 2014 Society for Neuroscience conference in Washington, D.C.
The brains of humans and some animals naturally synthesize endocannabinoids, molecules that help regulate functions including appetite, mood and response to stress. An ample supply of endocannabinoids keeps anxiety under control, and this is the function that Gray and her colleagues at the Hotchkiss Brain Institute at the University of Calgary want to boost.
When something stressful happens — a deadline approaches or travel plans go awry — the fight or flight response floods the brain with corticotropin-releasing hormone (CRH). It degrades endocannabinoids and turns anxiety on. That’s like releasing the parking brake when a car is parked on a hill. The new drug would boost the level of endocannabinoids in the brain, creating a buffer against CRH’s action.
Endocannabinoids and the active compounds in marijuana both bind to the same brain receptors, which is why some people self-medicate by smoking marijuana.
“Often, if you go to a Medical marijuana clinic and tell them you have anxiety, they’ll give you marijuana,” said James Lim, a neuroscientist at the University of California-Irvine. The problem is that cannabis also contains many other chemicals, including harmful tars, that complicate the reaction. If researchers can design an endocannabinoid-boosting compound that is simpler, said Gray, “we can better understand what people are exposing themselves to.”
Previously, researchers assumed that the stress “parking brake” system acted the same in everyone. But new research during the November conference points to a different model — that some people’s brains synthesize more endocannabinoids than others, and that people with higher levels can handle more stress.
Researchers have long known that some people can take more metaphorical heat than others. “Some kids can undergo a lot of traumatic events in early life and turn out just fine,” said University of Michigan researcher Pam Maras. “Some undergo relatively minor things and turn out to have severe anxiety and depression.”
Numerous researcher teams are using rat models to try to understand how stress responses can be manipulated, and they reported their findings at the conference.
In separate experiments, Gray and Lim tinkered with endocannabinoid levels in rats. Both found that rats with higher levels acted less anxious after being exposed to stress. Lim made part of a maze scary by tainting it with the scent of a fox’s feces. Rats with more stress-braking power would explore the tainted regions of the maze. More timid rats avoided it for as long as seven days after the scent was laid down.
Two other research groups, working independently in Ohio and Colorado, manipulated CRH levels in different ways but arrived at complementary results.
At Kent State University, neuroscientist Lee Gilman blocked CRH receptors in mice, shutting out the stress-inducing peptide and enabling them to approach other, unfamiliar mice.
At the University of Colorado-Boulder, Christopher Lowery is interested in how the brain responds to repeated social defeat. For example, what happens when a child is repeatedly bullied? He mimicked this by putting a male rat into the home cage of another male rat, where the newcomer would be forced to surrender to the more dominant native. In his study, rats that faced social defeat over and over produced more CRH each time, and were more quickly immobilized by fear during later encounters.
However, as Lim and Gilman both observed, some animals can put the brake on anxiety longer than others. Clinicians know this is true for humans; what the laboratory scientists are probing is when and how those differences manifest in the brain.
Michigan researcher Pam Maras sees evidence that these differences begin early in development. Her more nervous rats began displaying excessive anxiety as early as 11 days after birth, which corresponds to the fifth week of life for an infant. Animals that did not manifest anxiety at that point grew up to be more resilient to stress, though Maras can’t say why.
“We don’t have an answer for that right now,” said Maras. “It’s exciting sometimes when you don’t have an answer, because that means that there’s more to do.”
Some people are probably born more vulnerable to anxiety disorders than others. And although they might benefit greatly from a medication that puts a brake on runaway anxiety, scientists have a lot to learn before such a drug will be ready for clinical use.
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J. Megan Gray, PhD, Hotchkiss Brain Institute, University of Calgary.
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