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Science 6 October 2000:
Vol. 290. no. 5489, pp. 131 - 134
DOI: 10.1126/science.290.5489.131
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Reports

Molecular and Neuronal Substrate for the Selective Attenuation of Anxiety

Karin Löw,1*dagger Florence Crestani,1* Ruth Keist,1* Dietmar Benke,1 Ina Brünig,1 Jack A. Benson,1 Jean-Marc Fritschy,1 Thomas Rülicke,2 Horst Bluethmann,3 Hanns Möhler,1 Uwe Rudolph1ddagger

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 alpha 2 or alpha 3 GABAA (gamma -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 alpha 2(H101R) point mutation but present in mice with the alpha 3(H126R) point mutation. These findings indicate that the anxiolytic effect of benzodiazepine drugs is mediated by alpha 2 GABAA receptors, which are largely expressed in the limbic system, but not by alpha 3 GABAA receptors, which predominate in the reticular activating system.

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

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

ddagger    To whom correspondence should be addressed. E-mail: rudolph{at}pharma.unizh.ch

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Anxiety-Reducing Benzodiazepine Receptor Identified.
(2000)
Journal Watch (General) 2000, 7
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