Oct. 2, 2002 CHAPEL HILL -- Anxiety, a natural response to real or potential threats, affects all higher creatures, including humans, sometime in their lives. Under normal conditions, that protective emotion spurs action to avoid such threats.
But when anxiety grows excessive -- as it does in an estimated 25 percent of U.S. residents sooner or later -- it can significantly reduce one's quality of life, and in the cases of some 20 million Americans at any given time, it reaches levels that may require treatment.
"We have effective compounds already for treating anxiety that are some of the most commonly prescribed medications worldwide," said Dr. Clyde W. Hodge, associate professor of psychiatry at the University of North Carolina at Chapel Hill School of Medicine. "Among these are benzodiazepines, such as Valium. The problem with them, however, is that they act as sedatives, which often prevent people from functioning normally. And people can become addicted to them." As a result, he said, a worldwide search is on for less disruptive alternatives. Working with colleagues at the University of California at San Francisco, Hodge now may have good news about that search.
"What we've done is to identify a potential new target in the brain for new, less problematic anxiety-reducing medications of the future," Hodge said. Combining genetic, drug and behavioral studies in mice, he and his colleagues have found that mice lacking a form of the enzyme protein kinase C (PKC-epsilon) are extremely sensitive to their brains' own calming neurosteroid compounds and show significantly less anxiety than normal mice with PKC-epsilon, he said. The scientists conclude that inhibitors of PKC therefore may be useful in treating anxiety.
A report on the findings appears in the October issue of the Journal of Clinical Investigation. Besides Hodge, who is lead author, contributors include Drs. Jacob Raber now of Oregon Health and Science University in Portland, Robert O. Messing of the Ernest Gallo Clinic and Research Center at the University of California at San Francisco, who generated the genetically altered mice, and A. Leslie Morrow of UNC. Hodge and Morrow are members of UNC's Bowles Center for Alcohol Studies.
"In a paper in Nature Neuroscience in 1999, we showed that 'knockout' mice -- laboratory animals raised after their gene for PKC-epsilon had been intentionally disabled -- were super sensitive to modulation, or manipulation, of GABA, the number one inhibitory neurotransmitter in both mice and humans," he said. "As a result, they were more sensitive to alcohol and other drugs like Valium that alter GABA function. That led us to speculate about anxiety."
In new experiments involving mazes that both normal mice and mice with 'knocked out' PKC-epsilon scurried around in, researchers found the latter to be considerably less timid about open lighted areas and heights. The specially created rodents acted as if they already had been given medications to reduce their natural timidity, and they demonstrated a blunted response to stress as shown by lower stress hormone levels.
"The knockout mice also were more sensitive to a naturally occurring compound, allopregnanolone, which is called a neuroactive steroid and which alters GABA receptor function and hence has a calming effect," Hodge said. "GABA is what most of the known anxiety-lessening drugs act on in humans."
While obviously it would not be possible or desirable to knock out the PKC gene in humans, he said, medications could be developed that selectively inhibit PKC epsilon and modulate GABA differently from the existing imperfect drugs such as benzodiazepines with their sedative and addictive side effects.
"We don't know that yet, but this work gives us new hope," the scientist said.
In an accompanying commentary, Dr. Joshua A. Gordon of the Center for Neurobiology and Behavior at Columbia University's psychiatry department, praised the new findings.
"The exciting take-home message … is the idea that PKC should be considered as a potential target for (anxiety-reducing) therapy," Gordon wrote. "…It is attractive to imagine that PKC blockade would result in (anxiety reduction) by making our brains more sensitive to our own (naturally occurring compounds for keeping anxiety under control)."
The new research was supported by the State of California and various National Institutes of Health, including the National Institute for Alcoholism and Alcohol Abuse, grants to Hodge, Messing and Raber.
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