Taking Aim at Anxiety

Many psychoactive drugs are not very specific, and so even when they are effective, they come with a number of potentially unwanted side effects. Benzodiazepine tranquilizers, given to treat anxiety disorders and panic attacks, are no exception. In general, they act to enhance inhibitory signals in the brain mediated by the neurotransmitter GABA. But there are several types of GABA receptors to which the drug can bind. So scientists have wondered which ones play a role in actually quelling anxiety and which cause less desirable effects, such as motor impairment and sleepiness. Researchers from Switzerland and the U.S. give an answer to that question in today's Science.

Based on where different GABA receptors are located in the brain, the scientists suspected that alpha-2 GABA_A and alpha-3 GABA_A were the most likely of a tranquilizer's targets to be involved in dispelling symptoms of anxiety, its so-called anxiolytic effect. Alpha-2 GABA_A receptors are common in the cerebral cortex, striatum and limbic systemthe brain's emotional center; and alpha-3 GABA_A receptors are expressed, among other places, in neurons making neurotransmittersincluding serotonin and GABAimplicated in anxiety disorders. To test them both, the researchers created mice with either alpha-2 or alpha-3 receptors rendered insensitive to diazepam, or valium (above).

In both types of altered mice, the drug continued to act as a sedative and anticonvulsant and to impair motor skills. But they found significant differences when they compared the animals' behaviors during several tasks to that of genetically unaltered mice. Given the choice between a light and dark area, the wild-type mice spent more time in the light the more diazepam they received. So, too, for the animals with inactivated alpha-3 GABA_A receptors. The mice with modified alpha-2 GABA_A receptors, however, remained anxious and fled to the dark no matter how much diazepam they got. The drug also failed to decrease inhibition in this group in a maze test. Thus, the researchers conclude, "alpha-2 GABA_A receptors are highly specific targets for the development of future selective anxiolytic drugs."