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Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes - Nature

  • ️Möhler, Hanns
  • ️Thu Oct 21 1999
  • Letter
  • Published: 21 October 1999

Nature volume 401, pages 796–800 (1999)Cite this article

Abstract

GABAA (γ-aminobutyric acidA) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the spectrum of actions elicited by clinically effective drugs acting at their modulatory benzodiazepine-binding site. Here we show, by introducing a histidine-to-arginine point mutation at position 101 of the murine α1-subunit gene, that α1-type GABAA receptors, which are mainly expressed in cortical areas and thalamus1, are rendered insensitive to allosteric modulation by benzodiazepine-site ligands, whilst regulation by the physiological neurotransmitter γ-aminobutyric acid is preserved. α1(H101R) mice failed to show the sedative, amnesic and partly the anticonvulsant action of diazepam. In contrast, the anxiolytic-like, myorelaxant, motor-impairing and ethanol-potentiating effects were fully retained, and are attributed to the nonmutated GABAA receptors found in the limbic system (α2, α5), in monoaminergic neurons (α3) and in motoneurons (α2, α5)1. Thus, benzodiazepine-induced behavioural responses are mediated by specific GABAA receptor subtypes in distinct neuronal circuits, which is of interest for drug design.

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Acknowledgements

We thank Y. Lang for blastocyst injections, D. Blaser, S. Ganz, H. Pochetti and G. Schmid for animal care, R. Keist and C. Michel for technical assistance and H. Westphal for providing Ella-cre mice. This work was supported by a grant from the Swiss National Science Foundation.

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Authors and Affiliations

  1. Institute of Pharmacology, University of Zürich, and Swiss Institute of Technology (ETH), Winterthurestrasse 190, Zürich, CH-8057, Switzerland

    Uwe Rudolph, Florence Crestani, Dietmar Benke, Ina Brünig, Jack A. Benson, Jean-Marc Fritschy & Hanns Möhler

  2. Pharma Division, Preclinical Research, F. Hoffmann-LaRoche Ltd, Basel, CH-4002, Switzerland

    James R. Martin & Horst Bluethmann

Authors

  1. Uwe Rudolph

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  2. Florence Crestani

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  3. Dietmar Benke

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  4. Ina Brünig

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  5. Jack A. Benson

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  6. Jean-Marc Fritschy

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  7. James R. Martin

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  8. Horst Bluethmann

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  9. Hanns Möhler

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Correspondence to Uwe Rudolph.

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Rudolph, U., Crestani, F., Benke, D. et al. Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes. Nature 401, 796–800 (1999). https://doi.org/10.1038/44579

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  • Received: 02 June 1999

  • Accepted: 31 August 1999

  • Issue Date: 21 October 1999

  • DOI: https://doi.org/10.1038/44579

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