Valium and related drugs are among the world's most popular treatments for anxiety, despite numerous side effects. Now researchers have identified a receptor in the brain that's responsible for just the drug's antianxiety powers--opening up the possibility that a drug targeted to that receptor could ease anxiety without causing drowsiness, clumsiness, and memory loss.
The chemical compounds known as benzodiazepines, such as Valium, calm the brain by discouraging neurons from firing. The drugs boost the efficiency of a chemical messenger called GABA, which flips the brain's main "off switch." Four types of GABA receptors--the switches on the outside of neurons--are sensitive to benzodiazepines. Last year, a team led by Uwe Rudolph of the University of Zürich in Switzerland reported that, in mice, only one of those receptor types is responsible for benzodiazepines' side effect of sleepiness.
Next the researchers wanted to figure out which receptor sends the drugs' soothing signals. They engineered two mice strains with dysfunctional receptors. The two candidates, a2 and a3 receptors, show up in the parts of the brain that respond to fear. When the researchers interfered with the a3 receptor's ability to pick up Valium, the mice were completely normal. Given a dose of the drug, they were more likely to venture into new wings of a maze and well-lit places--a standard lab measure of lessened anxiety--than were undrugged mice. Mice with unresponsive a2 receptors, however, were equally anxious with or without Valium--suggesting that the a2 receptor is where the drug works to reduce anxiety, they report in the 6 October issue of Science.
Pharmacologists have worked for years to distill benzodiazepines' desirable effects, says neuroscientist Richard Olsen of the University of California, Los Angeles. Knowing that a2 receptors are where the drugs calm anxiety, he says, "we can and should be able to design drugs that selectively lower anxiety without putting you to sleep or impairing learning and memory."