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June 24, 2002

Davis scaring out causes and cures for phobias

By Poul Olson

Football commentator John Madden fears flying. Acclaimed singer Barbara Streisand fears public appearances. Ironically, even the head of the Center for Behavioral Neuroscience’s Fear Collabora-tory once was afraid of speaking in public.

“I eventually overcame my fear, but a lot of people never do,” said Michael Davis, Wood-ruff Professor of Psychiatry and Behavioral Science. “For some, excessive fear can be paralyzing and debilitating.”

As a behavioral neuroscientist, Davis has spent almost two decades puzzling out the brain systems and circuitry involved in fear. With this knowledge, one of his goals has been to develop a therapeutic adjunct to psychotherapy for people suffering from a range of disorders associated with the fear response.

Davis and his colleagues recently discovered what could be a significant breakthrough. Administering a drug called D-cycloserine (DCS), which has been used for years to treat tuberculosis, Davis successfully suppressed the fear response in rats that had been conditioned to associate the appearance of lights with an electric shock. DCS did not promote fear extinction in the absence of lights; instead, Davis found it had to be administered at the same time the lights—the fear stimulus—appeared.

Rats provide ideal models for understanding the fear response. Using classic fear conditioning, Davis teaches the rats to associate the appearance of a light with an electric shock. He can confirm that the animals are afraid because they are more easily startled by a loud sound when the light is on. By the same conditioning, he can extinguish their fear response after repeated episodes when the glow of the lights does not result in an electric shock.

In the early 1990s, Davis conducted two studies that revealed the central role of an area of the brain called the amygdala and the glutamate receptor N-methyl-D-aspartate (NMDA) in regulating the fear response. In the first experiment, Davis found that a drug that blocks the activity of the neurotransmitter glutamate at this NMDA receptor suppressed the rats’ ability to learn to fear the lights. A second study demonstrated that a similar NMDA antagonist prevented fear extinction. Despite the fact that an electric shock did not accompany the lights during multiple presentations, the rats continued to jump in anticipation of the shock.

Biochemical processes are clearly involved in the fear response, which can be quantitatively assessed by changes in heart rate, blood pressure, perspiration and the release of certain hormones. However Davis said that, in fact, most fears are learned.

“Fear memories probably never go away,” Davis said. “Instead, most people learn to deal with them or suppress them. DCS, when administered simultaneously with the presentation of the fear stimulus, basically promotes a new form of learning to cope with memories of an aversive event.”

Given that DCS is already FDA approved, Davis (and a research team that includes Fear Collaboratory members Kerry Ressler and Barbara Rothbaum) is planning a clinical trial to assess the drug’s ability to promote fear extinction in people suffering from a variety of phobias, anxiety, panic and post-traumatic stress disorders. The study will draw on Ressler’s and Rothbaum’s clinical experience in treating post-traumatic stress disorders and Rothbaum’s ability to create virtual-reality simulations of fear-inducing events.

For someone with an excessive fear of heights, Rothbaum has simulated a self-controlled glass elevator going up the outside of a 50-story building. Acrophobics initially can only rise to the second or third floor, but after several sessions, their fear begins to wane and they can go to higher floors.

“DCS should speed up this process,” Davis said. “Virtual-reality technology provides a well-controlled psychotherapeutic situation to see if DCS will improve the outcome of treating acrophobics and, hopefully, people suffering from more complex anxiety conditions, such as panic and post-traumatic stress disorders.”

While cautious about whether DCS can permanently extinguish a debilitating fear disorder, Davis sees much opportunity to explore the drug’s ability to treat a variety of psychological disorders, even drug addiction.

“The same sort of learned responses associated with fear are involved with drug craving,” Davis said. “The sight of drug paraphernalia or a street corner where the drugs were purchased are powerful cues that produce craving. DCS, in combination with psychotherapy, could be used to extinguish these connections and ultimately learn a new way to cope with craving.”

Davis’ study appeared this spring in The Journal of Neuroscience. His co-authors include David Walker, Ressler and Kwok-Tung Lu in psychiatry and behavioral sciences. The research is supported by the CBN and grants from the National Institute of Mental Health.