Molecular and Neuronal Substrate for the Selective Attenuation of Anxiety

Löw, Karin
Crestani, Florence
Keist, Ruth
Benke, Dietmar
Brünig, Ina
Benson, Jack A.
Fritschy, Jean-Marc
Rülicke, Thomas
Bluethmann, Horst
Möhler, Hanns
Rudolph, Uwe

¹Institute of Pharmacology and Toxicology, University of Zürich, and Swiss Federal Institute of Technology Zürich (ETH), Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. ²Biological Central Laboratory, University Hospital, Sternwartstrasse 6, CH-8091 Zürich, Switzerland. ³Department Pharma Research Gene Technology, F. Hoffmann-La Roche Ltd., CH-4002 Basel, Switzerland.

*These authors contributed equally to this report.

†Present address: Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

‡To whom correspondence should be addressed. E-mail: [email protected]

9 June 2000; accepted 10 August 2000

Science 290(5489):p 131-134, October 6, 2000.

Benzodiazepine tranquilizers are used in the treatment of anxiety disorders. To identify the molecular and neuronal target mediating the anxiolytic action of benzodiazepines, we generated and analyzed two mouse lines in which the α2 or α3 GABA_A (γ-aminobutyric acid type A) receptors, respectively, were rendered insensitive to diazepam by a knock-in point mutation. The anxiolytic action of diazepam was absent in mice with the α2(H101R) point mutation but present in mice with the α3(H126R) point mutation. These findings indicate that the anxiolytic effect of benzodiazepine drugs is mediated by α2 GABA_A receptors, which are largely expressed in the limbic system, but not by α3 GABA_A receptors, which predominate in the reticular activating system.