Pre-clinical study suggests how steroid can reverse post-traumatic stress
DALLAS — Sept. 12, 2006 — Researchers at UT Southwestern Medical Center, working with mice, have shown how the body's own natural stress hormone can help lastingly decrease the fearful response associated with reliving a traumatic memory.
Days after experiencing a traumatic event — a mild electrical shock — mice in the study still showed a fearful response when re-exposed to the place where it happened, a condition that could be a model for post-traumatic stress disorder in humans. But mice receiving the hormone corticosterone at the time they "relived" the event experienced a significant drop in that fear.
"Corticosterone appears to enhance new memories that compete with the fearful memory thereby decreasing its negative emotional significance," said Dr. Craig Powell, senior author and assistant professor of neurology and psychiatry at UT Southwestern. "When an animal or human is exposed to or relives an aversive scenario, a process called extinction creates a competing memory."
"We're not erasing memories," said Dr. Robert Greene, professor of psychiatry at UT Southwestern and another author of the study. "What the steroid does is attenuate the fear memory by helping the mice to learn that these contexts should no longer be perceived as dangerous."
The study is being published online and in the Sept. 13 issue of the Journal of Neuroscience.
While other researchers have tested such steroids clinically with some success for patients with disorders of emotional memories such as post-traumatic stress disorder (PTSD) and phobias, those studies did not control for a number of variables and were not designed to address the mechanism of the drug's action, Dr. Greene said.
This study focused on a mechanism called extinction, in which a memory gradually diminishes, but can be re-established by a small reminder of the original event.
"Our studies show that glucocorticoids work specifically to enhance the extinction of fear memory, as opposed to other mechanisms affecting recall, such as eliminating the memory entirely," said Dr. Greene. "This provides a proof of principle, and is an essential step in advancing this therapeutic approach."
A UT Southwestern study is now under way in collaboration with the Dallas VA Medical Center with veterans suffering from PTSD to see if receiving a stress hormone while reliving their memories can reduce their disabling fear responses to their traumatic memories.
"The natural release of stress hormones during recall of a fearful memory may be a natural mechanism to decrease the negative emotional aspects of the memory," said Dr. Jacqueline Blundell, a postdoctoral fellow in neurology at UT Southwestern and one of the paper's co-lead authors. "Conversely, patients with post-traumatic stress disorder have blunted stress hormone responses and thus may not decrease fearful memories normally over time."
In the published study, mice were placed in a plastic box and given an electrical shock to the feet equal to the standard protocol for this type of research. The shock, Dr. Powell said, is similar to a static electricity shock people experience when wearing socks on carpet and then touching metal. "Except that instead of a brief spark, it persists for two seconds," he said. "It's more than enough to scare you, makes you react briskly, and makes you hesitant to touch the door handle again."
The mice were returned to the box two days later, and their fear, gauged by how long they "froze" in place, remained high. A few minutes later, they were injected with the stress hormone corticosterone.
The day after the injection, when they were returned to the box, the mice showed significantly less fear. The strength of this effect depended on the dosage of the hormone given.
In order for the effect to work, the corticosterone had to be given after the mice were returned to the site of the initial trauma, causing the memory to be re-activated. Giving it beforehand or giving it without placing the mice in the box had no effect when tested a day later.
However, when the injections were given over four days, the timing became less important — giving the steroid either before or after secondary exposure to the box reduced fear.
Other UT Southwestern researchers involved in the study were Dr. Wen-Hui Cai, assistant professor of psychiatry; and Jie Han, research assistant in psychiatry.
The work was supported by the National Institute of Mental Health, the Conte Center, the National Alliance for Research on Schizophrenia and Depression, and the Department of Veterans Affairs.
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