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Science 290 (5489): 131-134

Copyright © 2000 by the American Association for the Advancement of Science

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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5-Ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahydrobenzo[4,5]imidazo[1,2a]pyridine-4-N- (2-fluorophenyl)carboxamide (RWJ-51204), a New Nonbenzodiazepine Anxiolytic.
B. Dubinsky, A. H. Vaidya, D. I. Rosenthal, C. Hochman, J. J. Crooke, S. DeLuca, A. DeVine, C. T. Cheo-Isaacs, A. R. Carter, A. D. Jordan, et al. (2002)
J. Pharmacol. Exp. Ther. 303, 777-790
   Abstract »    Full Text »    PDF »
Molecular and Pharmacological Characterization of GABAA Receptor alpha 1 Subunit Knockout Mice.
J. E. Kralic, E. R. Korpi, T. K. O'Buckley, G. E. Homanics, and A. L. Morrow (2002)
J. Pharmacol. Exp. Ther. 302, 1037-1045
   Abstract »    Full Text »    PDF »
Molecular Actions of (S)-Desmethylzopiclone (SEP-174559), an Anxiolytic Metabolite of Zopiclone.
M. W. Fleck (2002)
J. Pharmacol. Exp. Ther. 302, 612-618
   Abstract »    Full Text »    PDF »
Enhanced Learning and Memory and Altered GABAergic Synaptic Transmission in Mice Lacking the alpha 5 Subunit of the GABAA Receptor.
N. Collinson, F. M. Kuenzi, W. Jarolimek, K. A. Maubach, R. Cothliff, C. Sur, A. Smith, F. M. Otu, O. Howell, J. R. Atack, et al. (2002)
J. Neurosci. 22, 5572-5580
   Abstract »    Full Text »    PDF »
Trace fear conditioning involves hippocampal {alpha}5 GABAA receptors.
F. Crestani, R. Keist, J.- M. Fritschy, D. Benke, K. Vogt, L. Prut, H. Bluthmann, H. Mohler, and U. Rudolph (2002)
PNAS 99, 8980-8985
   Abstract »    Full Text »    PDF »
Transgenic Expression of a Mutant Glycine Receptor Decreases Alcohol Sensitivity of Mice.
G. S. Findlay, M. J. Wick, M. P. Mascia, D. Wallace, G. W. Miller, R. A. Harris, and Y. A. Blednov (2002)
J. Pharmacol. Exp. Ther. 300, 526-534
   Abstract »    Full Text »    PDF »
A New Benzodiazepine Pharmacology.
H. Mohler, J. M. Fritschy, and U. Rudolph (2002)
J. Pharmacol. Exp. Ther. 300, 2-8
   Abstract »    Full Text »    PDF »
New insights into the role of the GABAA--benzodiazepine receptor in psychiatric disorder.
D. J. NUTT and A. L. MALIZIA (2001)
The British Journal of Psychiatry 179, 390-396
   Abstract »    Full Text »    PDF »
SL651498: An Anxioselective Compound with Functional Selectivity for alpha 2- and alpha 3-Containing gamma -Aminobutyric AcidA (GABAA) Receptors.
G. Griebel, G. Perrault, J. Simiand, C. Cohen, P. Granger, M. Decobert, D. Francon, P. Avenet, H. Depoortere, S. Tan, et al. (2001)
J. Pharmacol. Exp. Ther. 298, 753-768
   Abstract »    Full Text »    PDF »
Perspectives on Neuroscience and Behavior.
(2001)
Neuroscientist 7, 91-92
   PDF »
Zolpidem, Triazolam, and Diazepam Decrease Distress Vocalizations in Mouse Pups: Differential Antagonism by Flumazenil and {beta}-Carboline-3-carboxylate-t-butyl ester ({beta}-CCt).
J. K. Rowlett, W. Tornatzky, J. M. Cook, C. Ma, and K. A. Miczek (2001)
J. Pharmacol. Exp. Ther. 297, 247-253
   Abstract »    Full Text »
Glutamic acid decarboxylase and glutamate receptor changes during tolerance and dependence to benzodiazepines.
E. Izzo, J. Auta, F. Impagnatiello, C. Pesold, A. Guidotti, and E. Costa (2001)
PNAS 98, 3483-3488
   Abstract »    Full Text »    PDF »
Molecular Targets for the Myorelaxant Action of Diazepam.
F. Crestani, K. Low, R. Keist, M.-J. Mandelli, H. Mohler, and U. Rudolph (2001)
Mol. Pharmacol. 59, 442-445
   Abstract »    Full Text »    PDF »
Anxiety-Reducing Benzodiazepine Receptor Identified.
(2000)
Journal Watch (General) 2000, 7
   Full Text »
Anxiety-Reducing Benzodiazepine Receptor Identified.
AL Komaroff and AL Komaroff (2000)
Journal Watch 2000, JW200010240000007
   Abstract »    Full Text »

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