Making Mice Mellow: Rodents yield clues to improved anxiety drugs

Treatments for anxiety disorders often center on drugs that relieve symptoms but can be addictive and cause drowsiness and other side effects. These medications work on brain-cell receptors for either of two chemical messengers, GABA or serotonin.

A new study has taken the first steps toward identifying drugs that may pack a more effective anxiety-fighting punch. Mice bred to lack the gene for an enzyme called protein kinase C epsilon (PKCe) display far more calmness and curiosity in stressful situations than do mice who possess the gene, according to a research team led by neuroscientist Robert O. Messing of the University of California, San Francisco.

The scientists theorize that the absence of PKCe enhances the sensitivity of GABA receptors to a class of messengers known as neurosteroids. This boosts GABA’s effectiveness at slowing down communication among neurons. Depletion of GABA has been linked to anxiety disorders.

Improved anxiety treatments may emerge if researchers develop medications that indirectly boost GABA’s influence by thwarting PKCe, Messing’s team concludes in the October Journal of Clinical Investigation.

“Our strategy is to see if we can influence GABA-receptor function through a [biochemical] side door that leads to the discovery of anti-anxiety medications with fewer side effects,” says study coauthor Clyde W. Hodge of the University of North Carolina at Chapel Hill.

In 1999, the scientists first studied so-called knockout mice missing a gene for PKCe. Compared with mice carrying the gene, the knockout animals displayed blunted withdrawal symptoms after regular alcohol consumption and were less likely to drink alcohol again if given the opportunity.

In the new study, Messing’s team turned up evidence that a GABA-mediated decline in anxiety may represent the fundamental attribute of these knockout mice. Mice lacking the gene PKCe showed few signs of fearfulness and a greater willingness to explore unfamiliar mazes–including one with unprotected pathways raised almost 2 feet off the floor–than did mice possessing the gene. PKCe-deprived mice also had lower blood concentrations of two stress hormones.

Moreover, injections of a substance that obstructs GABA-receptor activity rendered knockout mice as fearful and cautious in novel mazes as animals with intact PKCe genes were. Injections of the same substance had no effect on anxiety in the normal mice.

In contrast, injections of a druglike neurosteroid yielded more dramatic anxiety-related effects–including coordination-impairing drowsiness–in mice lacking PKCe than in normal mice.

The finding that PKCe deficiency in mice diminishes anxiety offers a promising lead in the search for improved drug treatments, comments neuroscientist Joshua A. Gordon of Columbia University.

Researchers now need to identify precise ways in which PKCe, as well as various neurosteroids, modifies GABA receptors, Gordon says. At the same time, Hodge says, to preempt potential side effects, it will be important to discern whether PKCe affects the heart and other organs.

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